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Background: Cardiovascular autonomic neuropathy (CAN) is known to affect patients with diabetes mellitus (DM) and cause adverse renal outcomes. We aimed to analyze the association between CAN and diabetic kidney disease (DKD)., Method: We enrolled 254 DM patients (mean age, 56.7 ± 15.2 years; male: female ratio, 1.17:1) with 19 (7.5%) type 1 DM patients and 235 (92.5%) type 2 DM patients. All patients had undergone cardiovascular autonomic function tests between January 2019 and December 2021 in a tertiary hospital in Korea. Cardiovascular autonomic neuropathy was categorized as normal, early, or definite after measuring three heart rate variability parameters. Diabetic kidney disease refers to a persistently elevated urinary albumin-creatinine ratio (uACR ≥30 mg/g) or reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m 2 ). Logistic and Cox regression analyses were performed., Results: Patients with elevated uACR (n=107) and reduced eGFR (n=32) had a higher rate of definite CAN. After adjusting for covariates, definite CAN was associated with elevated uACR (OR=2.4, 95% CI 1.07-5.36) but not with reduced eGFR (OR=3.43, 95% CI 0.62-18.90). A total of 94 patients repeated uACR measurements within 2 years (mean follow-up, 586.3 ± 116.8 days). Both definite and early CAN were independent risk factors for elevated uACR (HR=8.61 and 8.35, respectively; both p <0.05). In addition, high-density lipoprotein cholesterol, ACE inhibitors/angiotensin receptor blockers and glucagon-like peptide-1 receptor agonists were independent protective factors for elevated uACR (HR=0.96, 0.25, and 0.07, respectively; all p <0.05)., Conclusion: Cardiovascular autonomic neuropathy is a potential indicator of DKD. Comprehensive management of DKD in the early stages of CAN may prevent microalbuminuria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cho, Lim, Kwon, Chung, Moon, Yoon and Won.)

Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 μg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In China, the Astragalus membranaceus root is used to treat chronic kidney disease. Astragaloside IV (AS-IV), the primary bioactive compound, exhibits anti-inflammatory and antioxidative properties; however, its renoprotective mechanism in diabetic kidney disease (DKD) remains unclear. The study aimed to investigate the protective effects of AS-IV on DKD revealing the underlying mechanisms. We established an early diabetic rat model by feeding a high-fat diet and administering low-dose streptozotocin. Twelve weeks post-treatment, renal function was evaluated using functional assays, histological analyses, immunohistochemistry, western blotting, and transmission electron microscopy. HK-2 cells exposed to high glucose conditions were used to examine the effect of AS-IV on oxidative stress, iron levels, reactive oxygen species (ROS), and lipid peroxidation. Network pharmacology, proteomics, molecular docking, and molecular dynamics simulation techniques were employed to elucidate the role of AS-IV in DKD. The results revealed that AS-IV effectively enhanced renal function and mitigated disease pathology, oxidative stress, and ferroptosis markers in DKD rats. In HK-2 cells, AS-IV lowered the levels of lipid peroxides, Fe 2+ , and glutathione, indicating the repair of ferroptosis-related mitochondrial damage. AS-IV reduced mitochondrial ROS while enhancing mitochondrial membrane potential and ATP production, indicating its role in combating mitochondrial dysfunction. Overall, in silico analyses revealed that AS-IV interacts with HMOX1, FTH1, and TFR1 proteins, supporting its efficacy in alleviating renal injury by targeting mitochondrial dysfunction and ferroptosis. AS-IV may play a renoprotective role by regulating mitochondrial dysfunction and inhibiting. HMOX1/FTH1/TFR1-induced ferroptosis. Accordingly, AS-IV could be developed for the clinical treatment of DKD-related renal injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored., Aim of the Study: To elucidate the specific mechanism by which AS-IV moderates DKD progression., Materials and Methods: A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods., Results: AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells., Conclusions: AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Recently, podocyte mitochondrial dysfunction and necroptosis have been shown to play critical roles in renal fibrosis (RF) in diabetic kidney disease (DKD); however, these conditions lack effective treatment. In China, the supplemented Gegen Qinlian Decoction Formula (SGQDF), which originates from the classical prescription Gegen Qinlian Decoction, has been widely used to treat patients with DKD. However, it remains unclear whether SGQDF alleviates podocyte injury-associated RF in patients with DKD., Aim of Study: This study aimed to clarify the therapeutic effects of SGQDF compared with those of empagliflozin (EMPA) on podocyte mitochondrial fission and RF in DKD and its necroptosis-related mechanisms., Materials and Methods: Modified DKD rat models were developed through a combination of uninephrectomy, streptozotocin administration through intraperitoneal injection, and exposure to a high-fat diet. Following RF formation, the DKD rat models received either a high dose of SGQDF (H-SGQDF), a low dose of SGQDF (L-SGQDF), EMPA, or vehicle for 4 weeks. In our in vitro study, we subjected cultured murine podocytes to a high-glucose environment and various treatments including Mdivi-1, adalimumab, and necrostatin-1, with or without H-SGQDF or EMPA. SGQDF target prediction and molecular docking verification were performed. For the in vivo study, we focused on examining changes in the parameters associated with renal injury, RF, and oxidative stress (OS)-induced injuries in podocytes. Both in vivo and in vitro studies included an analysis of changes in podocyte mitochondrial fission, TNF-α-induced podocyte necroptosis, and the RIPK1/RIPK3/MLKL signaling pathway activation., Results: SGQDF improved renal injury markers, including body weight, blood glucose, serum creatinine, blood urea nitrogen, and urinary albumin, in a dose-dependent manner. The beneficial effects of H-SGQDF in vivo were greater than those of L-SGQDF alone in vivo. Interestingly, similar to EMPA, H-SGQDF ameliorated RF and reduced OS-induced podocyte injury in diabetic kidneys. Furthermore, TNF-α signaling was shown to be important in the network construction of "the SGQDF-component-target." Based on this, we also showed that the beneficial effects in vivo and in vitro of H-SGQDF were closely related to the improvement in mitochondrial dysfunction and the inhibition of TNF-α-induced necroptosis in podocytes., Conclusion: In the present study, we showed that H-SGQDF, similar to EMPA, attenuates podocyte mitochondrial fission and RF, and that the underlying therapeutic mechanisms are closely related to inhibiting the activation of the RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. Our findings provide new pharmacological evidence for the application of H-SGQDF in the RF treatment of DKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The gut microbiome-metabolites-kidney axis is a potential target for treating diabetic kidney disease (DKD). Our previous study found that Liraglutide attenuated DKD in rats by decreasing renal tubular ectopic lipid deposition (ELD) and serum metabolites levels, including L-5-Oxoproline (5-OP). However, the response of gut microbiome-metabolites-kidney axis to Liraglutide in DKD rats and the effect of 5-OP on ELD remain unknown. In this study, Sprague-Dawley rats were used as an animal model of DKD. They were subjected to a high fat diet, streptozotocin and uninephrectomy, followed by Liraglutide treatment (0.4 mg/kg d). Additionally, HK-2 cells were incubated with 30 mM glucose and 200 μM palmitate for 24h, and exposed to different concentrations of 5-OP. In DKD rats, Liraglutide dramatically improved the renal tubule structure. It increased the Simpson index (F = 4.487, p = 0.035) and reduced the Actinobacteria-to-Bacteroidetes ratio (F = 6.189, p = 0.014). At the genus level, Liraglutide increased the relative abundance of Clostridium, Oscillospira, Sarcina, SMB53, and 02d06 while decreasing that of Allobaculum. Meanwhile, 13 metabolites were significantly altered after Liraglutide treatment. Multi-omics analysis found that 5-OP levels were positively correlated with Clostridium abundance but negatively correlated with renal injury related indicators. In HK-2 cells, 5-OP significantly reduced the ELD in a dose-dependent manner through inhibiting the expression of SREBP1 and FAS. Overall, the renoprotective effect of Liraglutide in DKD rats is linked to the improvement of the gut microbiota composition and increased serum 5-OP levels, which may reduce ELD in renal tubular cells by lowering lipid synthesis., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Reactive oxygen species production might be prevented by xanthine oxidoreductase (XOR) inhibitors, which can cause glomerulosclerosis. We aimed to investigate whether topiroxostat, an XOR inhibitor, prevents diabetic kidney disease development in mice. Six-week-old control Institute of Cancer Research (ICR) mice and type 2 diabetic Nagoya Shibata Yasuda (NSY) mice were divided into the ICR group (ICR mice which received a lard-containing high-fat diet [HFD] based on the AIN-93G diet), NSY control group (NSY mice which received the same aforementioned diet), and NSY + topiroxostat group (NSY mice which received the same aforementioned diet with addition of 0.0012% topiroxostat). After 20 weeks, plasma biomarkers, XOR activity and oxidative stress levels, which were assessed using malondialdehyde (MDA), were measured through enzyme-linked immunosorbent assay or enzymatic methods. Renal pathology was evaluated using periodic acid-Schiff staining. Redox gene and protein expression were determined using RT-qPCR and western blotting, respectively. Plasma XOR activity was lower in NSY mice treated with topiroxostat than those without. Plasma cystatin C and creatinine levels did not differ between the ICR and NSY control groups or between the NSY control and NSY + topiroxostat groups. The NSY + topiroxostat group showed a smaller mesangial area than the NSY control group. The mRNA expression of Sod3, Prdx1, Gpx2, and Gpx3 was higher in the NSY + topiroxostat group than in the NSY control group. Renal MDA levels were lower in the NSY + topiroxostat group than in the NSY control group. Topiroxostat can reduce glomerulosclerosis, and the reduction is associated with renal oxidative markers., Competing Interests: Declaration of competing interest T. Nakmura is an employee of Pharmacological Study Group Pharmaceutical Research Laboratories, and he contributed to providing topiroxostat and determining XOR activity. Commercial organizations, including Pharmacological Study Group Pharmaceutical Research Laboratories, did not fund the study. None of the other authors have conflicts of interest or financial disclosures to the present study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD., (© 2024. The Author(s).)

The role of Neutrophil extracellular traps (NETs) in the immunopathogenesis of Diabetic Kidney Disease (DKD) remains elusive. We used a machine learning approach to identify differentially expressed genes (DEGs) associated with NETs in human DKD kidney biopsy datasets and validated the results using single-nucleus RNA sequencing datasets. The expressions of these candidate genes and related cytokines were verified in blood obtained from DKD patients. Three NETs-associated genes (ITGAM, ITGB2 and TLR7) were identified, which all showed significant upregulation in both glomerular and tubulointerstitial compartments in human DKD kidneys. DKD patients showed significantly higher number of activated neutrophils with increased ITGAM and ITGB2 expression, higher serum IL-6 but lower IL-10, compared to healthy controls (p all <0.01). This study suggests that dysregulation of NETs-associated genes ITGAM and ITGB2 are related to the pathogenesis of DKD, and may serve as novel diagnostic markers and therapeutic targets in DKD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dysfunctional renal tubular epithelial cells, induced by high glucose, are commonly observed in the kidney tissues of diabetic nephropathy (DN) patients. The epithelial-mesenchymal transition (EMT) of these cells often leads to renal interstitial fibrosis and kidney damage in DN. High glucose also triggers mitochondrial damage and apoptosis, contributing further to the dysfunction of renal tubular epithelial cells. Cellular senescence, a recognized characteristic of DN, is primarily caused by high glucose. However, it remains unclear whether high glucose-induced cellular senescence in DN exacerbates the functional impairment of tubular epithelial cells. In this study, we examined the relationship between EMT and cellular senescence in kidney tissues from streptozotocin (STZ)-induced DN and HK-2 cells treated with high glucose (HG). We also investigated the impact of HG concentrations on tubular epithelial cells, specifically mitochondrial dysfunction, cellular senescence and apoptosis. These damages were primarily associated with the secretion of cytokines (such as IL-6, and TNF-α), production of reactive oxygen species (ROS), and an increase of intracellular Ca 2+ . Notably, resveratrol, an anti-aging agent, could effectively attenuate the occurrence of EMT, mitochondrial dysfunction, and apoptosis induced by HG. Mechanistically, anti-aging treatment leads to a reduction in cytokine secretion, ROS production, and intracellular Ca 2+ levels., Competing Interests: Declaration of competing interest All authors declare no competing interests. We declare that neither the entire paper nor any part of its content has been published or has been accepted elsewhere. If accepted, it will not be published elsewhere in the same form, in English or in any other languages, including electronic form without the written consent of the copyright-holder., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Type 1 diabetes (T1D) increases the risk of chronic kidney disease (CKD) development. The aims of this study were to classify trajectories of estimated glomerular filtration rate (eGFR) in a cohort of Canadian adults with T1D, and to describe the risk factors associated with declining eGFR trajectories., Methods: In this retrospective cohort of adults with T1D, data was collected between 1996 and 2020. CKD was defined as eGFR <60 mL/min/1.73 m 2 . Latent class mixed models were used to categorize eGFR trajectories. Multinomial logistic regression was used to identify factors associated with declining eGFR trajectories., Results: In this study, 304 adults were analyzed, with baseline measurements at a median duration of T1D of 15.3 (5.4-24.2) years. Eight percent of the cohort developed CKD over a median duration of 24.3 (13.7-34.8) years. Four classes of longitudinal eGFR trajectories were identified, broadly categorized as steeply declining (SD1, SD2) and gradual declining (GD1, GD2). Female sex, poor glycemic control, elevated body mass index, and albuminuria were associated with a steeply declining trajectory., Conclusion: In this cohort, four distinctive eGFR trajectories were identified, including a subtype with steeply declining eGFR. Given the complex nature of CKD progression, further prospective study of this model for identification of individuals at risk for CKD based on their trajectory of kidney function may support clinicians in their decision-making., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Constadina Panagiotopoulos reports financial support was provided by Juvenile Diabetes Research Foundation (JDRF) Centre of Excellence. Kristen Favel reports financial support was provided by University of British Columbia Faculty of Medicine Clinician Investigator Program. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Diabetic kidney disease (DKD) is influenced by multiple factors, yet its precise progression mechanisms remain largely unclear. This study aimed to create a clinical risk-scoring system based on genetic polymorphisms in the AFF3, CARS, CERS2, ERBB4, GLRA3, RAET1L, TMPO, and ZMIZ1 genes., Methods: The study included a DKD group diagnosed with diabetic kidney disease before age 18 and a WDC group matched by age, gender, and age at diabetes diagnosis. Genetic data and clinical data from diabetes diagnosis to moderately increased albuminuria (MIA) detection were compared between the groups., Results: Among 43 DKD cases, 22 were girls and 21 were boys. At MIA diagnosis, mean body weight SDS was -0.24 ± 0.94, height SDS was 0.34 ± 1.15, and BMI SDS was -0.26 ± 0.94. Systolic blood pressure was at the 72nd percentile (2-99), and diastolic blood pressure was at the 74th percentile (33-99). Significant differences in rs267734, rs267738, and rs942263 polymorphisms were found between DKD and non-complication diabetic groups (13[30.2 %] vs 5[11.6 %], p = 0.034; 14[32.6 %] vs 5[11.6 %], p = 0.019; 26[60.5 %] vs 40[93 %], p < 0.001)., Conclusion: Several factors were identified as significant in DKD onset, including low follow-up weight SDS, elevated diastolic blood pressure, presence of rs267734, and absence of rs942263 polymorphisms. The model demonstrated a specificity of 81.4 % and a sensitivity of 74.4 %., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ferda Evin reports financial support, article publishing charges, statistical analysis, and writing assistance were provided by Ege University Scientific Research Projects. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end‑stage renal disease, and is characterized by persistent proteinuria and decreased glomerular filtration rate. Despite extensive efforts, the increasing incidence highlights the urgent need for more effective treatments. Histone methylation is a crucial epigenetic modification, and its alteration can destabilize chromatin structure, thereby regulating the transcriptional activity of specific genes. Histone methylation serves a substantial role in the onset and progression of various diseases. In patients with DKD, changes in histone methylation are pivotal in mediating the interactions between genetic and environmental factors. Targeting these modifications shows promise in ameliorating renal histological manifestations, tissue fibrosis and proteinuria, and represents a novel therapeutic frontier with the potential to halt DKD progression. The present review focuses on the alterations in histone methylation during the development of DKD, systematically summarizes its impact on various renal parenchymal cells and underscores the potential of targeted histone methylation modifications in improving DKD outcomes.

The prognosis of acute kidney injury (AKI) is markedly worse in patients with diabetes. Diabetes not only exaggerates the severity of AKI but also prevent kidney repair or recovery from AKI. Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Specifically, diabetes increases AKI severity, making it difficult to induce the same level of AKI in diabetic and nondiabetic animals to compare their kidney repair. Here, we have identified a time window of 4 days immediately after the completion of streptozotocin (STZ) treatment in mice when blood glucose has yet to rise. Within this time window, renal ischemia-reperfusion injury (IRI) induced the same level of AKI in STZ-treated mice [127.2 ± 12.82 mg/dL blood urea nitrogen (BUN), 2.275 ± 0.4728 serum creatinine] and vehicle solution-treated mice (128.6 ± 11.83 mg/dL BUN, 2.087 ± 0.4748 mg/dL serum creatinine]. By days 5-6 , the post-AKI kidney entered into the phase of kidney repair when diabetic hyperglycemia started in STZ-treated mice, providing the opportunity to study the effect of diabetes on kidney repair without affecting initial AKI. In this model, kidney repair was indeed impaired by diabetes (116.5 ± 8.052 mg/dL BUN and 1.382 ± 0.2732 mg/dL serum creatinine in IR + vehicle group; 136.6 ± 8.740 mg/dL BUN and 1.916 ± 0.3756 mg/dL serum creatinine in IR + STZ group). The impairment was associated with decreased tubular cell proliferation and increased tubular cell senescence, peritubular capillary (PTC) rarefaction, inflammation, and 40.90% more interstitial fibrosis. NEW & NOTEWORTHY Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Here, we report a mouse model to investigate the effect of diabetes on kidney repair without affecting initial injury and found that the repair defect is associated with decreased renal tubular cell proliferation and increased tubular cell senescence, PTC rarefaction, inflammation, and interstitial fibrosis.

The underlying causes of diabetic kidney disease are still largely unknown. New insights into the contributing causes of diabetic nephropathy are important to prevent this complication. Hyperglycemia and hypertension are some of the risk factors for diabetic nephropathy. However, the incidence of diabetic nephropathy is increasing despite efforts to normalize blood glucose levels and blood pressure. Therefore, other factors should be investigated as causes of diabetic nephropathy. We investigated whether long-term increased plasma levels of glucagon contribute to the development of pathophysiological changes in kidney function as seen in patients with diabetic nephropathy. Using mouse models of chronic activation and inactivation of glucagon receptor signaling, we investigated whether glucagon is involved in changes in renal function, renal structure, and transcriptional changes. We found several histopathological changes in the kidney, such as thickening of the parietal layer of Bowman's capsule, glomerular mesangial cell expansion, and significant albuminuria in the mice with activated glucagon receptor signaling. Opposite effects on mesangial area expansion and the development of albuminuria were demonstrated in mice with glucagon receptor inactivation. RNA sequencing data revealed that transcription of genes related to fatty acid metabolism, podocytes, Na + -K + -ATPase, and sodium/glucose transport was significantly changed in mice with activated glucagon receptor signaling. These data implicate that glucagon receptor signaling is involved in the development of kidney injury, as seen in type 2 diabetes, and that glucagon receptor is a potential therapeutic target in the treatment of diabetes. NEW & NOTEWORTHY This study suggests that the glucagon receptor is a potential therapeutic target in the treatment of diabetic kidney disease. We show, in mice, that long-term treatment with a glucagon analog showed not only pathophysiological changes and changes in renal function but also transcriptional changes in the kidneys, whereas opposite effects were demonstrated in mice with glucagon receptor inactivation. Therefore, the use of glucagon in a treatment regimen requires investigation of possible metabolic and renal abnormalities.

Diabetic patients as well as the elderly are known to have high pulse pressure (PP), but there are few studies on how microangiopathy and macroangiopathy are involved in its mechanism. In this study, we examined the association between PP and atherosclerotic lesions by vessel size in kidney biopsy tissue and examined how PP is associated with kidney prognosis. This retrospective observational study included 408 patients with biopsy-proven diabetic nephropathy at Nara Medical University Hospital. Exposure of interest was PP measured at kidney biopsy. Outcome variable was kidney failure with replacement therapy (KFRT). Cox proportional hazards and competing risk regression models with all-cause mortality as a competing event were used to examine these associations. A total of 408 patients were divided into tertiles based on PP (mmHg): Tertile 1 (reference), <51; Tertile 2, 51-64; and Tertile 3, >64. Among the 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. Higher PP was independently associated with higher incidences of KFRT (hazard ratio [95% confidence interval] for Tertile 3 vs. Tertile 1; 2.07 [1.05-4.09]. In histological lesions, PP was strongly associated with glomerular lesions, tubulointerstitial lesions, and arteriolar hyalinosis (all ps for trend <0.001), but not with intimal thickening (p for trend = 0.714). PP was significantly associated with diabetic glomerular/tubulointerstitial lesions and arteriolar hyalinosis but not with intimal thickening at the time of kidney biopsy and was also significantly associated with subsequent KFRT in patients with diabetic nephropathy., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus, characterized by complex pathogenesis that involves numerous molecules and signaling pathways. Among these, CD2 glycoprotein and CD44 play pivotal roles in cell adhesion, signal transduction, and inflammatory responses, potentially contributing significantly to the onset and progression of DN. This study aimed to investigate the central features of CD2 glycoprotein and CD44 in preventing diabetic nephropathy. To achieve this, kidney tissue sample data from DN patients were sourced from a public gene expression database. The roles of CD2 glycoprotein and CD44 within the PPI network were then analyzed, focusing on their interactions with other related genes. WGCNA analysis identified several significant gene modules associated with DN, including CD2 glycoprotein and CD44. PPI network analysis showed that these two proteins had a high degree of connectivity in the network, suggesting that they may be central regulatory molecules of DN. Further functional enrichment analysis revealed the potentially important role of CD2 glycoprotein and CD44 in diabetic nephropathy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic kidney disease, known as diabetic nephropathy (DN), is a widespread severe diabetes complication leading to kidney failure. Due to the lack of efficacious therapies, this study endeavors to enhance DN therapeutic effectiveness of ferulic acid (FRA), a natural phenolic with poor oral bioavailability, by developing a transdermal kidney-targeted spanlastic formulation. Spanlastics (SP) nanovesicles were prepared using Span 60 and Labrasol or Brij35 as edge activators (EA). Cationic guar (CG) and hyaluronic acid (HA) were employed as coatings. The formulations were assessed for entrapment efficiency (EE), particle size (PS) and zeta potential (ZP). A 2 1  × 3 1 factorial optimization of FRA spanlastic formulations revealed the desirable nanoformula was FRA-L-H-SP comprising Labrasol and hyaluronate coating. Transmission electron microscopy (TEM), Fourier-transform infrared (FT-IR), Diphenylpicrylhydrazyl (DPPH) antioxidant activity, in-vitro release, and rat skin ex-vivo permeation assessed this formula and the uncoated one (FRA-L-SP). Biochemical indicators and histopathology for diabetes and kidney injury were evaluated in the Streptozotocin (STZ)-induced DN rat model. Results showed significant improvements after treatment with FRA-L-H-SP compared to FRA-L-SP and free FRA, with decreased blood glucose, creatinine, and intercellular adhesion molecule-1 (ICAM-1) levels and increased insulin, AMP-activated protein kinase (AMPK), and sirtuins (SIRT). This enhancement can be acknowledged as passive targeting of SP and active targeting properties of hyaluronic to cluster of differentiation 44 (CD44) receptors, revealing the potential to improve DN pathophysiology., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To assess the association between glycated haemoglobin (HbA1c) variability and risk of renal function decline in type 2 diabetes mellitus (T2DM)., Research Design and Methods: A comprehensive search was carried out in PubMed, Embase, Web of Science and the Cochrane Library (until 12 March 2024). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines were followed for this meta-analysis. HbA1c variability was presented as indices of the standard deviation (SD), coefficient of variation (CV), HbA1c variability score (HVS) and haemoglobin glycation index (HGI). This meta-analysis was performed using random-effect models., Results: Eighteen studies met the objectives of this meta-analysis. The analyses showed positive associations between HbA1c variability and kidney function decline, with hazard ratio (HR) 1.26 (95% confidence interval [CI] 1.15-1.38) for high versus low SD groups, HR 1.47 (95% CI 1.30-1.65) for CV groups, HR 1.32 (95% CI 1.10-1.57) for HVS groups and HR 1.53 (95% CI 1.05-2.23) for HGI groups. In addition, each 1% increase in SD and CV was linked to kidney function decline, with HR 1.26 (95% CI 1.17-1.35), and 1.13 (95% CI 1.03-1.23), respectively. Also, each 1-SD increase in SD of HbA1c was associated with deterioration in renal function, with HR 1.17 (95% CI 1.07-1.29)., Conclusions: The four HbA1c variability indicators were all positively associated with renal function decline progression; therefore, HbA1c variability might play an important and promising role in guiding glycaemic control targets and predicting kidney function decline progression in T2DM., (© 2024 John Wiley & Sons Ltd.)

Aim: To assess the likelihood of dementia in individuals with type 2 diabetes (T2D), distinguishing between those with and without microvascular diseases., Methods: Leveraging the National Health Insurance Research Database in Taiwan, we identified individuals newly diagnosed with T2D from 1 January 2009 through 31 December 2014. Multivariable Cox proportional hazard models were used to compare the risk of outcomes., Results: Individuals with microvascular disease had a significantly higher risk of all-cause dementia (adjusted hazard ratio [95% confidence interval] 1.13 [1.09, 1.17]) compared with matched individuals without microvascular disease. In addition, individuals with diabetic kidney disease and diabetic neuropathy were associated with a significantly increased risk of Alzheimer's disease (1.16 [1.02, 1.32] and 1.14 [1.03, 1.27]), vascular dementia (1.21 [1.06, 1.38] and 1.14 [1.02, 1.28]) and other dementia (1.11 [1.04, 1.19] and 1.10 [1.04, 1.16]), respectively, compared with those without microvascular disease., Conclusions: This nationwide cohort study showed that patients with T2D and microvascular disease, particularly diabetic kidney disease and diabetic neuropathy, were associated with a significantly higher risk of Alzheimer's disease, vascular dementia, other dementia and all-cause dementia than those without microvascular disease., (© 2024 John Wiley & Sons Ltd.)

Demonstrating drug efficacy in slowing kidney disease progression requires large clinical trials when targeting participants with an early stage of chronic kidney disease (CKD). In this randomized, parallel-group, open-labeled trial (CANPIONE study), we assessed the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin using the individual's change in estimated glomerular filtration rate (eGFR) slope before (pre-intervention slope) and during treatment (chronic slope). We randomly assigned (1:1) participants with type 2 diabetes, urinary albumin-to-creatinine ratio (UACR) of 50 to under 300 mg/g, and an eGFR of at least 45 ml/min/1.73m 2 to receive canagliflozin or guideline-recommended treatment except for SGLT2 inhibitors (control). The first and second primary outcomes were the geometric mean percentage change from baseline in UACR and the change in eGFR slope, respectively. Of 98 randomized participants, 96 received at least one study treatment. The least-squares mean change from baseline in log-transformed geometric mean UACR was significantly greater in the canagliflozin group than the control group (between group-difference, -30.8% (95% confidence interval -42.6 to -16.8). The between-group difference (canagliflozin group - control group) of change in eGFR slope (chronic - pre-intervention) was 4.4 (1.6 to 7.3) ml/min/1.73 m 2 per year, which was more pronounced in participants with faster eGFR decline. In summary, canagliflozin reduced albuminuria and the participant-specific natural course of eGFR decline in participants with type 2 diabetes and microalbuminuria. Thus, the CANPIONE study suggests that the within-individual change in eGFR slope may be a novel approach to determine the kidney protective potential of new therapies in early stages of CKD., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Diabetic nephropathy (DN) is a common and serious complication of diabetes, contributing significantly to patient mortality. Complication of DN (CDN) ranks as the second leading cause of end-stage renal disease globally. To address this, understanding the genetic regulation underlying DN is crucial for personalized treatment strategies. In this study, we identified genes and lncRNAs associated with diabetes and diabetic nephropathy constructing a DN-related lncRNA-mRNA network (DNLMN). This network, characterized by scale-free biomolecular properties, generated through the study of topological properties, elucidates key regulatory interactions. Enrichment analysis of important network modules revealed critical biological processes and pathways involved in DN pathogenesis. In the second step, we investigated the differential expression and co-expression of hub nodes in diseased and normal individuals, identifying lncRNA-mRNA relationships implicated in disease regulation. Finally, we gathered DN-related single nucleotide polymorphisms (SNPs) and lncRNAs from the LincSNP 3.0 database. The DNLMN encompasses SNP-associated lncRNAs, and transcription factors (TFs) linked to differentially expressed lncRNAs between diseased and normal samples. These results underscore the significance of biomolecular networks in disease progression and highlighting the role of biomolecular variability contributes to personalized disease phenotyping and treatment.

Chronic kidney disease (CKD) is a major global health problem, affecting about 9.5% of the population and 850 million people worldwide. In primary care, most CKD is caused by diabetes and/or hypertension, but a substantial proportion of cases may have alternative causes. During the early stages, CKD is asymptomatic, and many people are unaware that they are living with the disease. Despite the lack of symptoms, CKD is associated with elevated risks of cardiovascular disease, progressive kidney disease, kidney failure and premature mortality. Risk reduction strategies are effective and cost-effective but require early diagnosis through testing of the estimated glomerular filtration rate and albuminuria in high-risk populations. Once diagnosed, the treatment of CKD centres around lifestyle interventions, blood pressure and glycaemic control, and preventative treatments for cardiovascular disease and kidney disease progression. Most patients with CKD should be managed with statins, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. Additional treatment options to reduce cardiorenal risk are available in patients with diabetes, including glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists. The Kidney Failure Risk Equation is a new tool that can support the identification of patients at high risk of progressive kidney disease and kidney failure and can be used to guide referrals to nephrology. This review summarizes the latest guidance relevant to managing adults with, or at risk of, CKD and provides practical advice for managing patients with CKD in primary care., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Diabetic Kidney Disease (DKD) is a complex disease associated with circadian rhythm and biological clock regulation disorders. Melatonin (MT) is considered a hormone with renal protective effects, but its mechanism of action in DKD is unclear., Methods: We used the GSE151325 dataset from the GEO database for differential gene analysis and further explored related genes and pathways through GO and KEGG analysis and PPI network analysis. Additionally, this study used a type 2 diabetes db/db mouse model and investigated the role of melatonin in DKD and its relationship with clock genes through immunohistochemistry, Western blot, real-time PCR, ELISA, chromatin immunoprecipitation (ChIP), dual-luciferase reporter technology, and liposome transfection technology to study DEC1 siRNA., Results: Bioinformatics analysis revealed the central position of clock genes such as CLOCK, DEC1, Bhlhe41, CRY1, and RORB in DKD. Their interaction with key inflammatory regulators may reveal melatonin's potential mechanism in treating diabetic kidney disease. Further experimental results showed that melatonin significantly improved the renal pathological changes in db/db mice, reduced body weight and blood sugar, regulated clock genes in renal tissue, and downregulated the TLR2/MyD88/NF-κB signaling pathway. We found that the transcription factor DEC1 can bind to the TLR2 promoter and activate its transcription, while CLOCK's effect is unclear. Liposome transfection experiments further confirmed the effect of DEC1 on the TLR2/MyD88/NF-κB signaling pathway., Conclusion: Melatonin shows significant renal protective effects by regulating clock genes and downregulating the TLR2/MyD88/NF-κB signaling pathway. The transcription factor DEC1 may become a key regulatory factor for renal inflammation and fibrosis by activating TLR2 promoter transcription. These findings provide new perspectives and directions for the potential application of melatonin in DKD treatment., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

The role of aldosterone has yet to be well appreciated in chronic kidney disease (CKD). Two variables define CKD: an estimated glomerular filtration rate of <60 ml/min/1.73 m 2 and a spot urine albumin-creatinine ratio of >30 mg/g. Both are needed for an accurate diagnosis. The presence of CKD at this level is associated with an elevated risk of cardiovascular death and a greater risk of CKD progression to kidney failure and subsequent dialysis. This paper presents an overview of aldosterone's importance in CKD and its contribution to the inflammatory processes involved in CKD development. Data on outcomes, both surrogate and hard, related to outcomes on CKD progression will also be discussed in the context of mineralocorticoid blockade. Based on recent epidemiological data as well as data examining markers of diabetic kidney disease progression, it is clear that use of both renin-angiotensin system inhibitors and aldosterone receptor antagonists have a significant role in altering the natural history of kidney disease progression itself, as well as reducing the risk of cardiovascular events that generally accompany long-standing kidney disease. This paper will discuss these issues and the management of consequent hyperkalaemia when both steroidal and non-steroidal mineralocorticoid receptor antagonists are used in detail., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Diabetic kidney disease (DKD) significantly impairs quality of life in individuals with diabetes mellitus (DM). The influence of the Dietary Inflammatory Index (DII) on DKD, which is associated with adverse health outcomes, is not well-understood., Methods: We analyzed 2712 subjects from the National Health and Nutrition Examination Survey (NHANES) spanning 2011-2018, aiming to elucidate the relationship between DII and DKD., Results: DKD was diagnosed in 1016 participants (37.46%). Elevated DII levels were significantly associated with an increased DKD risk, as evidenced by multivariate logistic regression (Odds Ratio [OR] = 1.40, 95% Confidence Interval [CI] 1.12-1.75, P < 0.05). Further analysis after adjusting for covariates highlighted a notable non-linear correlation between DII and DKD risk, at DII values below 0.45, the risk of DKD increases with higher DII levels, whereas it stabilizes beyond this point. Subgroup analysis additionally revealed that diabetic men have a significantly higher DKD risk compared to women (P < 0.05)., Conclusion: Our study indicates a pronounced link between higher DII scores and increased risk of DKD among DM patients. These findings underscore the paramount importance of dietary management in DM treatment, stressing the need for interventions focused on reducing dietary inflammation to decelerate DKD progression., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6 -/- ) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Background: Diabetic Nephropathy is one of the most severe complications of Diabetes Mellitus and the main cause of end-stage kidney disease worldwide. Despite the therapies available to control blood glucose and blood pressure, many patients continue to suffer from progressive kidney damage. Chronic hyperglycemia is the main driver of changes observed in diabetes; however, it was recently discovered that inflammation and oxidative stress contribute to the development and progression of kidney damage. Therefore, it is important to search for new pharmacological therapies that stop the progression of DN. Sodium tungstate (NaW) is an effective short and long-term antidiabetic agent in both type 1 and type 2 diabetes models., Methods: In this study, the effect of NaW on proinflammatory signalling pathways, proinflammatory proteins and fibrosis in the streptozotocin (STZ)-induced type 1 diabetic rat model was analysed using histological analysis, western blotting and immunohistochemistry., Results: NaW treatment in diabetic rats normalize parameters such as glycemia, glucosuria, albuminuria/creatinuria, glomerular damage, and tubulointerstitial damage. NaW decreased the proinflammatory signaling pathway NF-κB, inflammatory markers (ICAM-1, MCP-1 and OPN), profibrotic pathways (TGFβ1/Smad2/3), reduced epithelial-mesenchymal transition (α -SMA), and decreased renal fibrosis (type IV collagen)., Conclusion: NaW could be an effective drug therapy for treating human diabetic nephropathy., Competing Interests: Declaration of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Calcium-independent phospholipase A2γ (iPLA2γ) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis, deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy. Hyperglycemia was induced in male mice with streptozotocin (STZ). STZ induced progressive albuminuria in control mice (over 21 weeks), while albuminuria did not increase in iPLA2γ KO mice, remaining comparable to untreated groups. Despite similar exposure to STZ, the STZ-treated iPLA2γ KO mice developed a lower level of hyperglycemia compared to STZ-treated control. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even iPLA2γ KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in diabetic control mice. Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in diabetic control compared to diabetic iPLA2γ KO mice. Glomerular matrix was expanded in diabetic mice, with control exceeding iPLA2γ KO. Glomerular autophagy (increased LC3-II and decreased p62) was enhanced in diabetic iPLA2γ KO mice compared to control. Treatment of cultured GECs with H2O2 resulted in increased cell death in control GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with high glucose compared to low glucose. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. In conclusion, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This is associated with increased glomerular autophagy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cybulsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous studies have shown that paricalcitol (PA) has a protective effect on the kidneys. However, the exact molecular mechanism by which PA affects diabetic nephropathy (DN) progression remains uncertain. PBMCs of patients with DN were isolated, and CYP2J2 and VDR levels were detected by qPCR. Pearson correlation analysis was utilized to detect the relationship between uACR and CYP2J2 and VDR and between CYP2J2 and VDR. The protective effects of PA on DN have been examined by TUNEL, HE staining, ELISA, and Flow cytometry assays in STZ-induced mice. Moreover, THP-1 cells were stimulated with HG/LPS for in vitro studies. ELISA, qPCR, western blot, and Flow cytometry assays were utilized to assess the effects of PA on DN progression by regulating CYP2J2. The interaction between CYP2J2 and VDR was analyzed by CHIP-qPCR and luciferase experiments. CYP2J2 and VDR levels were downregulated and uACR level was upregulated in DN patients. CYP2J2 and VDR were positively correlated in PBMCs. Both CYP2J2 and VDR are inversely correlated with uACR. Moreover, after PA treatment, 11, 12-EET levels increased, inflammatory factor levels decreased, and M2 macrophage polarization was promoted in STZ-induced mice and HG/LPS-triggered THP-1 cells. Depletion of CYP2J2 and VDR decreased 11, 12-EET level, enhanced inflammatory factor levels, and inhibited M2 macrophage polarization, which were reversed by CYP2J2 overexpression in HG/LPS-treated cells. Furthermore, VDR bound to the CYP2J2 promoter and promoted CYP2J2 transcriptional expression. The present work pointed out a new use for PA to inhibit DN progression by increasing EET level, inhibiting inflammatory response, and inducing M2 macrophage polarization via regulating the VDR/CYP2J2 axis., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Sedentary behavior, such as excessive sitting, increases risk of cardiovascular disease and premature mortality in the general population, but this has not been assessed in type 1 diabetes. Occupational sitting is increasingly ubiquitous and often constitutes the largest portion of daily sitting time. Our aim was to identify clinical factors associated with excessive occupational sitting in type 1 diabetes and, in a prospective setting, to explore its association with cardiovascular events and all-cause mortality, independent of leisure-time physical activity., Methods: An observational follow-up study of 1,704 individuals (mean age 38.9 ± 10.1 years) from the Finnish Diabetic Nephropathy Study. Excessive occupational sitting, defined as ≥ 6 h of daily workplace sitting, was assessed using a validated self-report questionnaire. Data on cardiovascular events and mortality were retrieved from national registries. Multivariable logistic regression identified independently associated factors, while Kaplan-Meier curves and Cox proportional hazard models were used for prospective analyses., Results: Factors independently and positively associated with excessive occupational sitting included a high occupational category [OR 6.53, 95% CI (4.09‒10.40)] and older age [1.02 (1.00‒1.03)], whereas negatively associated factors included current smoking [0.68 (0.50‒0.92)], moderate albuminuria [0.55 (0.38‒0.80)], and high leisure-time physical activity [0.52 (0.36‒0.74)]. During a median follow-up of 12.5 (6.5-16.4) years, 163 individuals (9.6%) suffered cardiovascular events, and during a median follow-up of 13.7 (9.4-16.6) years, 108 (6.3%) deaths occurred. Excessive occupational sitting increased cardiovascular event risk (hazard ratio [HR] 1.55 [95% CI 1.10‒2.18]) after adjustment for confounders and other covariates. Furthermore, in a stratified multivariable analysis among current smokers, excessive occupational sitting increased the risk of all-cause mortality (2.06 [1.02‒4.20])., Conclusions: Excessive occupational sitting is associated with a higher risk of cardiovascular events and all-cause mortality in individuals with type 1 diabetes. This association persists regardless of leisure-time physical activity, after adjusting for independently associated variables identified in our cross-sectional analyses. These findings underscore the need to update physical activity guidelines to better address sedentary behavior and improve outcomes for individuals with type 1 diabetes. Targeting occupational sitting should be considered a key focus for interventions aimed at reducing overall sedentary time., (© 2024. The Author(s).)

Objective: The objective of this study is to investigate the diagnostic utility of microRNAs (miRNAs) for distinguishing between urine samples from patients with Diabetic Kidney Disease (DKD) and those with Focal Segmental Glomerulosclerosis (FSGS)., Methods: In this multicentric, cross-sectional investigation, we enrolled patients diagnosed with DKD, individuals with primary biopsy-proven FSGS, and healthy controls. The top 5 miRNAs (hsa-mir-21, hsa-mir-30a, hsa-mir-193a, hsa-mir-196a, hsa-mir-200a) were selected to quantify miRNAs in urine samples. Isolation of targeted miRNAs was performed from urinary exosomes, and the quantitative profile of the isolated miRNAs was measured by RT-qPCR. The ΔΔCt method was implemented to calculate the fold differences between disease and control samples., Results: Thirteen DKD patients, 11 FSGS patients, and 14 healthy controls were included in this study. Hsa-mir-21 and hsa-mir-30a exhibited distinct regulation in both groups, with upregulation observed in FSGS and downregulation in DKD (hsa-mir-21 in DKD (0.668 ± 0.25, p < 0.0005) and FSGS (2.267 ± 1.138, p < 0.0077); hsa-mir-30a in DKD (0.874 ± 0.254, p = 0.079) and FSGS (1.378 ± 0.312, p < 0.0006)). Hsa-mir-193a exhibited significant dysregulation in DKD (1.017 ± 0.413, p < 0.029) but not in FSGS (4.18 ± 1.528, p = 0.058). Hsa-mir-196a and hsa-mir-200a showed upregulation in patient groups (hsa-mir-196a in DKD (1.278 ± 0.527, p = 0.074) and FSGS (2.47 ± 0.911, p < 0.0003); hsa-mir-200a in DKD (1.909 ± 0.825, p = 0.082) and FSGS (1.301 ± 0.358, p < 0.008))., Conclusion: Specific miRNAs, particularly miR-21, miR-30a, miR-196a, and miR-200a, might play a role in the pathogenesis of kidney diseases and could potentially serve as biomarkers to distinguish between FSGS and DKD patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Trabulus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ethnopharmacological Relevance: Toona sinensis (A. Juss.) Roem. Is a deciduous woody plant native to Eastern and Southeastern Asia. Different parts of this plant have a long history of being applied as traditional medicines to treat various diseases. The fruits have been used for antidiabetic, antidiabetic nephropathy (anti-DN), antioxidant, anti-inflammatory, and other activities., Aim of the Study: The purpose of this study was to investigate the effects of EtOAc (PEAE) and n-BuOH extracts (PNBE) from T. sinensis pericarps (TSP) on kidney injury in high-fat and high-glucose diet (HFD)/streptozotocin (STZ)-induced DN mice by network pharmacology and pharmacological investigations, as well as to further discover active compounds that could ameliorate oxidative stress and inflammation, thereby delaying DN progression by regulating the Nrf2/NF-κB pathway in high glucose (HG)-induced glomerular mesangial cells (GMCs)., Materials and Methods: The targets of TSP 1-16 with DN were analyzed by network pharmacology. HFD/STZ-induced DN mouse models were established to evaluate the effects of PEAE and PNBE. Six groups were divided into normal, model, PEAE100, PEAE400, PNBE100, and PNBE400 groups. Fasting blood glucose (FBG) levels, organ indices, plasma MDA, SOD, TNF-α, and IL-6 levels, as well as renal tissue Nrf2, HO-1, NF-κB, TNF-α, and TGF-β1 levels were determined, along with hematoxylin-eosin (H&E) and immunohistochemical (IHC) analysis of kidney sections. Furthermore, GMC activity screening combined with molecular docking was utilized to discover active compounds targeting HO-1, TNF-α, and IL-6. Moreover, western blotting assays were performed to validate the mechanism of Nrf2 and NF-κB in HG-induced GMCs., Results: Network pharmacology predicted that the main targets of PEAE and PNBE in the treatment of DN include IL-6, INS, TNF, ALB, GAPDH, IL-1β, TP53, EGFR, and CASP3. Additionally, major pathways include AGE-RAGE and IL-17. In vivo experiments, treatment with PEAE and PNBE effectively reduced FBG levels and organ indices, while plasma MDA, SOD, TNF-α, and IL-6 levels, renal tissue Nrf2, HO-1, NF-κB, TNF-α, and TGF-β1 levels, and renal function were significantly improved. PEAE and PNBE significantly improved glomerular and tubule injury, and inhibited the development of DN by regulating the levels of oxidative stress and inflammation-related factors. In vitro experiments, compound 11 strongly activated HO-1 and inhibited TNF-α and IL-6. The molecular docking results revealed that compound 11 exhibited a high binding affinity towards the targets HO-1, TNF-α, and IL-6 (<-6 kcal/mol). Western blotting results showed compound 11 effectively regulated Nrf2 and NF-κB p65 protein levels, and significantly improved oxidative stress damage and inflammatory responses in HG-induced GMCs., Conclusion: PEAE, PNBE, and their compounds, especially compound 11, may have the potential to prevent and treat DN, and are promising natural nephroprotective agents., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Accumulation of extracellular matrix (ECM) proteins in the glomerular mesangial region is a typical hallmark of diabetic nephropathy (DN). However, the molecular mechanism underlying ECM accumulation in the mesangium of DN patients remains unclear. The present study aims to establish a connection between extracellular proteins and DN with the goal of identifying potential biomarkers for this condition., Methods: Differentially expressed genes (DEGs) between DN kidney tissue and healthy kidney tissue were analyzed using the public data GSE166239. Two gene lists encoding extracellular proteins were then utilized to identify extracellular protein-differentially expressed genes (EP-DEGs). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed on these EP-DEGs. A protein-protein interaction (PPI) network was established to identify key EP-DEGs. Furthermore, the diagnostic ability, immune cell infiltration, and clinical relevance of these EP-DEGs were investigated. Immunohistochemistry (IHC) staining of paraffin-embedded renal tissues was performed to validate the accuracy of the bioinformatic results., Results: A total of 1204 DEGs were identified, from which 162 EP-DEGs were further characterized by overlapping with extracellular protein gene lists. From the PPI network analysis, five EP-DEGs (e.g., TNF, COL1A1, FN1, MMP9, and TGFB1) were identified as candidate biomarkers. TNF, COL1A1, and MMP9 had a high diagnostic accuracy for DN. Assessment of immune cell infiltration revealed that the expression of TNF was positively associated with resting dendritic cells (DCs) (r = 0.85, P < 0.001) and M1 macrophages (r = 0.62, P < 0.05), whereas negatively associated with regulatory T cells (r = - 0.62, P < 0.05). Nephroseq v5 analysis demonstrated a negative correlation between the estimated glomerular filtration rate (eGFR) and TNF expression (r = - 0.730, P = 0.025). Gene set enrichment analysis (GSEA) revealed significant enrichment of glycosaminoglycan (GAG) degradation in the high-TNF subgroup. IHC staining of renal tissues confirmed significantly elevated TNF-a expression and decreased hyaluronic acid (HA) levels in the DN group compared to controls (both P < 0.05), with a negative correlation observed between TNF-a and HA (r = - 0.691, P = 0.026)., Conclusion: Our findings suggest that TNF may play a pivotal role in the progress of DN by driving ECM accumulation, and this process might involve GAG degradation pathway activation., (© 2024. The Author(s).)

Background: Podocyte injury causes proteinuria and accelerates glomerular sclerosis during diabetic kidney disease (DKD). Disruptor of telomeric silencing 1-like (DOT1L), an evolutionarily conserved histone methyltransferase, has been reported in preventing kidney fibrosis in chronic kidney disease models. However, whether DOT1L exerts beneficial effects in diabetes induced podocyte injury and the underlying molecular mechanisms need further exploration., Methods: The expression of DOT1L was confirmed by Western blotting in MPC-5 cells and cortex of kidney from db/db mice, as well as immunofluorescence staining in human renal biopsy samples. The effect of DOT1L on podocyte injury was obtained using MPC-5 cells and db/db mice. The potential target genes regulated by DOT1L was measured by RNA-sequencing. Then, a series of molecular biological experiments was performed to investigate the regulation of PLCL1 by DOT1L in MCP-5 cells and db/db mice. Lipid accumulation was assessed by UPLC-MS/MS analysis and Oil Red O staining., Results: DOT1L expression was significantly declined in high glucose (HG)-treated MPC-5 cells, podocyte regions of kidney tissues from db/db mice and human renal biopsy samples. Subsequent investigations revealed that upregulation of DOT1L ameliorated HG-induced cell apoptosis in MPC-5 cells as well as primary podocytes. Furthermore, podocyte-specific DOT1L overexpression inhibited diabetic podocyte injury in db/db mice. Mechanistically, we revealed that DOT1L upregulated phospholipase C-like 1 (PLCL1) expression by mediating H3K79me2 at its promoter and PLCL1 silencing suppressed the protective role of DOT1L on podocyte injury. Moreover, DOT1L improved diabetes induced abnormal fatty acid metabolism in podocytes and PLCL1 knockdown reversed its protective effects., Conclusions: Taken together, our results indicate that DOT1L protects podocyte injury via PLCL1-mediated fatty acid metabolism and provides new insights into the therapeutic target of DKD., (© 2024. The Author(s).)

Diabetic nephropathy (DN) is one of the leading clinical causes of end-stage renal failure. The classical aldose reductase (AR) inhibitor epalrestat shows beneficial effect on renal dysfunction induced by DN, with metabolic profile and molecular mechanisms remains to be investigated further. In the current study, integrated untargeted metabolomics, network pharmacology and molecular dynamics approaches were applied to explore the therapeutic mechanisms of epalrestat against DN. Firstly, untargeted serum and urine metabolomics analysis based on UPLC-Q-TOF-MS was performed, revealed that epalrestat could regulate the metabolic disorders of amino acids metabolism, arachidonic acid metabolism, pyrimidine metabolism and citrate cycle metabolism pathways after DN. Subsequently, metabolomics-based network analysis was carried out to predict potential active targets of epalrestat, mainly involving AGE-RAGE signaling pathway, TNF signaling pathway and HIF-1 signaling pathway. Moreover, a 100 ns molecular dynamics approach was employed to validate the interactions between epalrestat and the core targets, showing that epalrestat could form remarkable tight binding with GLUT1 and NFκB than it with AR. Surface-plasmon resonance assay further verified epalrestat could bind GLUT1 and NFκB proteins specifically. Overall, integrated system network analysis not only demonstrated that epalrestat could attenuate DN induced metabolic disorders and renal injuries, but also revealed that it could interact with multi-targets to play a synergistic regulatory role in the treatment of DN., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A Chronic Kidney Disease (CKD) Epidemiology Collaboration (EPI) formula not including a Black race coefficient has been recently developed and is now recommended in the US. The new (2021) equation was shown to yield higher estimated glomerular filtration rate (eGFR) values than the old (2009) one in a non-Black general population sample, thus reclassifying a significant number of individuals to a better eGFR category. However, reclassified individuals were previously shown to have a lower risk of progression to end-stage kidney disease, but higher adjusted risks for all-cause death and morbidity and mortality from cardiovascular disease than those not reclassified. This study evaluated the prognostic impact of switching from the 2009 to the 2021 CKD-EPI equation in non-Black individuals with type 2 diabetes., Methods: The Renal Insufficiency And Cardiovascular Events (RIACE) was a prospective cohort study enrolling 15,773 Caucasian patients in 19 Italian centers in 2006-2008. Cardiometabolic risk profile, treatments, complications, and comorbidities were assessed at baseline and eGFR was calculated with the two equations. Vital status was retrieved on 31 October 2015 for 15,656 participants (99.3%)., Results: With the 2021 equation, the eGFR value increased in all patients, except for 293 individuals with a 2009 eGFR ≥ 105 ml·min - 1 ·1.73 m - 2 . The median difference was 4.10 ml·min - 1 ·1.73 m - 2 and was higher in males, older individuals and those in the G2 category. Reclassification decreased the percentage of patients with reduced eGFR from 17.28 to 13.96% and with any CKD from 36.23 to 34.03%. Reclassified individuals had better cardiometabolic risk profile and lower prevalence of complications and use of medications than non-reclassified individuals. Risk of death versus the 2009 G1 category was lower for reclassified than non-reclassified participants in all eGFR categories and, particularly, in each 2009 eGFR category, though difference was significant only in the G4-G5 category. The Receiver Operator Characteristic curves were statistically, but not clinically different with the two equations., Conclusion: Changing from the 2009 to the 2021 CKD-EPI equation results in higher eGFR and lower CKD prevalence, with a lower risk of death in reclassified patients with an eGFR < 30 ml·min - 1 ·1.73 m - 2 , but virtually no impact on mortality prediction., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008., (© 2024. The Author(s).)

Aims: According to the gut-kidney axis theory, gut microbiota (GM) has bidirectional crosstalk with the development of diabetic kidney disease (DKD). However, empirical results have been inconsistent, and the causal associations remain unclear. This study was aimed at exploring the causal relationship between GM and DKD as well as the glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). Materials and Methods: Two-sample Mendelian randomisation (MR) analysis was performed with inverse-variance weighting as the primary method, together with four additional modes (MR-Egger regression, simple mode, weighted mode, and weighted median). We utilised summary-level genome-wide association study statistics from public databases for this MR analysis. Genetic associations with DKD were downloaded from the IEU Open GWAS project or CKDGen consortium, and associations with GM (196 taxa from five levels) were downloaded from the MiBioGen repository. Results: In forward MR analysis, we identified 13 taxa associated with DKD, most of which were duplicated in Type 2 diabetes with renal complications but not in Type 1 diabetes. We observed a causal association between genetic signature contributing to the relative abundance of Erysipelotrichaceae UCG003 and that for both DKD and GFR. Similarly, host genetic signature defining the abundance of Ruminococcaceae UCG014 was found to be simultaneously associated with DKD and UACR. In reverse MR analysis, the abundance of 14 other GM taxa was affected by DKD, including the phylum Proteobacteria, which remained significant after false discovery rate correction. Sensitivity analyses revealed no evidence of outliers, heterogeneity, or horizontal pleiotropy. Conclusion: Our findings provide compelling causal genetic evidence for the bidirectional crosstalk between specific GM taxa and DKD development, contributing valuable insights for a comprehensive understanding of the pathological mechanisms of DKD and highlighting the possibility of prevention and management of DKD by targeting GM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Yun Zhang et al.)

Diabetic nephropathy is one of the most frequent complications of diabetic patients and is the leading cause of end-stage renal disease worldwide. The complex physiopathology of this complication raises a challenge in the development of effective medical treatments. Therefore, a better understanding of this disease is necessary for producing more targeted therapies. In this work we propose human amylin as a possible mediator in the development of diabetic nephropathy. Islet amyloid polypeptide or amylin is a hormone co-secreted with insulin. The human isoform has the ability to fold and form amyloid aggregates in the pancreas of patients with type 2 diabetes mellitus, disrupting cellular homeostasis due to its ability to form pores in lipid bilayers. It has been described that hIAPP can be secreted and exported in extracellular vesicles outside the pancreas, being a plausible connecting mechanism between the β-cell and other peripheral tissues such as the kidney. Here, we demonstrate that tubular, podocytes and mesangial cells can incorporate hIAPP coming from β-cells. Then, this hIAPP can form aggregates inside these kidney cells, contributing to its failure. In order to study the consequences in vivo, we found amylin aggregates in the kidney of mice overexpressing hIAPP after feeding a high fat diet. In addition, we observed an increase in glomerulosclerosis index and inflammation. Specifically, there were significant changes in signalling pathways directly involved in the diabetic nephropathy such as an increased in mTORC1 signaling pathway, an alteration in mitochondrial dynamics and an increased in endoplasmic reticulum stress. All these results demonstrate the importance of hIAPP in the kidney and its possible contribution in the development of diabetic nephropathy., (© 2024. The Author(s).)

Folates play a crucial role as cofactors in metabolic pathways, influencing biological methylation and nucleotide synthesis, which has a significant impact on overall health and disease susceptibility. Diabetic nephropathy (DN) is a prevalent and severe complication of diabetes mellitus (DM). The correlation between RBC folate and DN remains unclear currently. This study aims to assess whether RBC folate is associated with DN. Based on data from the NHANES (2011-2018), we conducted a cross-sectional study involving 3070 adults with type 2 DM (T2DM). Demographic factors, levels of folate and vitamin B12, dietary folate intakes, and relevant laboratory data were obtained from all participants. Logistic regression, fitting smooth curves, interaction effects were utilized to support the research objectives. Regression analyses demonstrated a positive relation between RBC folate and DN. (P < 0.001). A positive association between levels of RBC folate and the risk of DN was observed after full adjustment for all the confounding variables (odds ratio: 1.38, 95% confidence interval: 1.27-1.49, P < 0.001). Similar patterns of association were observed for subgroup analysis (all P values for interaction > 0.05). In addition, curve fitting after adjusting for all the confounding variables demonstrated that there was a linear relationship between RBC folate and DN (P for non-linearity = 0.147). Increased RBC folate levels were linked to a higher risk of DN in type 2 diabetes. RBC folate should be considered as a crucial indicator for folate status in DN., (© 2024. The Author(s).)

Inflammation, oxidative stress, fibrosis, and ferroptosis play important roles in diabetic nephropathy development. Krüppel-like factor 4 (KLF4) is a transcriptional factor, which regulates multiple cell processes and is involved in diabetic nephropathy. Berberine has various biological activities, including anti-inflammation, antioxidative stress, and antiferroptosis. Berberine has been shown to inhibit diabetic nephropathy, but whether it involves KLF4 and ferroptosis remains unknown. We established a diabetic nephropathy mice model and administered berberine to the mice. The kidney function, renal structure and fibrosis, expression of KLF4 and DNA methylation enzymes, DNA methylation of the KLF4 promoter, mitochondria structure, and expression of oxidative stress and ferroptosis markers were analyzed. Berberine rescued kidney function and renal structure and prevented renal fibrosis in diabetic nephropathy mice. Berberine suppressed the expression of DNMT1 and DNMT2 and upregulated KLF4 expression by preventing KLF4 promoter methylation. Berberine inhibited the expression of oxidative stress and ferroptosis markers, maintained mitochondria structure, and prevented ferroptosis. Berberine ameliorates diabetic nephropathy by inhibiting Klf4 promoter methylation and ferroptosis.

Diabetic nephropathy (DN) is a severe complication of prolonged diabetes, impacting millions worldwide with an increasing incidence. This study investigates the role of tribbles pseudokinase 3 (TRIB3), a protein implicated in the progression of DN, focusing on its mechanisms underlying glomerular damage. Through analysis of the Gene Expression Omnibus (GEO) database, we identified TRIB, among differentially expressed genes (DEGs) in streptozotocin (STZ)-treated C57BL/6J mice. Both in vitro and in vivo experiments were conducted to examine the effects of TRIB3 inhibition on high glucose (HG)-induced damage in podocytes and DN mouse models. The results demonstrated that TRIB3 inhibition reduced inflammatory responses and extracellular matrix (ECM) production inMPC5 cells, mediated by the downregulation of DNA damage-inducible transcript 3 (DDIT3) - a critical regulator of proinflammatory cytokine secretion and ECM synthesis. Inhibiting TRIB3 decreased inflammatory factors and ECM deposition in diabetic mice in vivo, confirming its pivotal role in DN pathogenesis. These findings indicate that TRIB3 and its interaction with DDIT3 contribute significantly to DN by promoting inflammatory cascades and ECM accumulation, presenting potential therapeutic targets for managing the disease.

Propionate metabolism is important in the development of diabetes, and fibrosis plays an important role in diabetic nephropathy (DN). However, there are no studies on biomarkers related to fibrosis and propionate metabolism in DN. Hence, the current research is aimed at evaluating biomarkers associated with fibrosis and propionate metabolism and to explore their effect on DN progression. The GSE96804 (DN : control = 41 : 20) and GSE104948 (DN : control = 7 : 18) DN-related datasets and 924 propionate metabolism-related genes (PMRGs) and 656 fibrosis-related genes (FRGs) were acquired from the public database. First, DN differentially expressed genes (DN-DEGs) between the DN and control samples were sifted out via differential expression analysis. The PMRG scores of the DN samples were calculated based on PMRGs. The samples were divided into the high and low PMRG score groups according to the median scores. The PM-DEGs between the two groups were screened out. Second, the intersection of DN-DEGs, PM-DEGs, and FRGs was taken to yield intersected genes. Random forest (RF) and recursive feature elimination (RFE) analyses of the intersected genes were performed to sift out biomarkers. Then, single gene set enrichment analysis was conducted. Finally, immunoinfiltrative analysis was performed, and the transcription factor (TF)-microRNA (miRNA)-mRNA regulatory network and the drug-gene interaction network were constructed. There were 2633 DN-DEGs between the DN and control samples and 515 PM-DEGs between the high and low PMRG score groups. In total, 10 intersected genes were gained after taking the intersection of DN-DEGs, PM-DEGs, and FRGs. Seven biomarkers, namely, SLC37A4, ACOX2, GPD1, angiotensin-converting enzyme 2 (ACE2), SLC9A3, AGT, and PLG, were acquired via RF and RFE analyses, and they were found to be involved in various mechanisms such as glomerulus development, fatty acid metabolism, and peroxisome. The seven biomarkers were positively correlated with neutrophils. Moreover, 8 TFs, 60 miRNAs, and 7 mRNAs formed the TF-miRNA-mRNA regulatory network, including USF1-hsa-mir-1296-5p-AGT and HIF1A-hsa-mir-449a-5p-ACE2. The drug-gene network contained UROKINASE-PLG, ATENOLOL-AGT, and other interaction relationship pairs. Via bioinformatic analyses, the risk of fibrosis and propionate metabolism-related biomarkers in DN were explored, thereby providing novel ideas for research related to DN diagnosis and treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Sha Li et al.)

Background: Observational studies have demonstrated the alterations of gut microbiota composition in diabetic nephropathy (DN), however, the correlation between gut microbiota and DN remains unclear., Methods: A two-sample Mendelian randomization (MR) analysis was designed to estimate the association between gut microbiota and DN. The summary statistics of gut microbiota from phylum level to genus level were obtained from a large-scale, genome-wide association study involving 18,340 individuals, and the data at the species level was derived from the study of TwinsUK Registry, including 1126 twin pairs. The summary statistics of DN were originated from the latest release data of FinnGen (R7, 299623 participants). The MR estimation was calculated using inverse variance weighted, weighted median, MR-Egger regression, and MR-PRESSO. Heterogeneity was assessed using Cochrane's Q test., Results: Inverse variance weighted results indicated that the order Bacteroidetes and its corresponding class and phylum [odds ratio (OR), 1.58; 95% confidence interval (CI), 1.15-2.17], the family Verrucomicrobiaceae and its corresponding class and order (OR, 1.46; 95% CI, 1.14-1.87), the genera Akkermansia (OR, 1.46; 95% CI, 1.14-1.87) and Catenibacterium (OR, 1.33; 95% CI, 1.07-1.66) might be associated with a higher risk of DN; whereas the genera Coprococcus2 (OR, 0.68; 95% CI, 0.51-0.91) and Eubacterium&#95;coprostanoligenes&#95;group (OR, 0.69; 95% CI, 0.52-0.92) might play protective roles in DN., Conclusions: This MR study suggested that several gut bacteria were potentially associated with DN, further studies are required to validate these findings., (© 2024. The Author(s).)

Background: The objective of our research was to investigate the specific mechanism of FTO in diabetic kidney disease (DKD) progression., Methods: The DKD model was established with renal tubular epithelial HK-2 cells and mice in vitro and in vivo. The N6-methyladenosine (m 6 A) content in cells was detected using dot plot assay and the m 6 A levels of NLRP3 was detected with the MeRIP assay. The mRNA and protein levels were tested with real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot. The IL-1β and IL-18 levels were assessed with enzyme-linked immunosorbent assay (ELISA). The cell viability was measured by cell counting kit (CCK)-8 assay and cell pyroptosis was determined with Annexin V and propidium iodide (PI) double staining followed by flow cytometry analysis. RNA-binding protein immunoprecipitation (RIP) and dual luciferase reporter assays were conducted to detect the interaction between FTO and NLRP3. m 6 A levels were detected by Me-RIP assay. The renal injury was measured by observing the renal morphology and urine and blood levels of relevant indicators., Results: The results indicated that high glucose treatment induced HK-2 cell pyroptosis. m 6 A levels were prominently elevated in high glucose treated HK-2 cells while FTO expression were significantly down-regulated. FTO over-expression promoted cell viability but inhibited pyroptosis of HK-2 cells under high glucose (HG) treatment. Moreover, FTO could inhibit NLRP3 expression. RIP and Me-RIP assays indicated that FTO could bind with NLRP3 and regulate its m 6 A modification level. Further luciferase assay confirmed that FTO binds with the 233-237 bp region of NLRP3. NLRP3 neutralized the function of FTO in the HG stimulated HK-2 cells. In vivo, the H&E staining showed that FTO over-expression alleviated the kidney injury and suppressed the pyroptosis induced by DKD., Conclusion: We found that FTO could inhibit the DKD progression in vivo and in vitro by regulated the m 6 A modification of NLRP3., (© 2024. The Author(s).)

Among all nephropathies, diabetic kidney disease (DKD) is the most common cause of kidney impairment advancement to end-stage renal disease (ESRD). Although DKD has no cure, the disease is commonly managed by strict control of blood glucose and blood pressure, and in most of these cases, kidney function often deteriorates, resulting in dialysis, kidney replacement therapy, and high mortality. The difficulties in finding a cure for DKD are mainly due to a poor understanding of the underpinning complex cellular mechanisms that could be identified as druggable targets for the treatment of this disease. The review is thus aimed at giving insight into the interconnection between chronic hyperglycaemia and cellular mechanistic perturbations of nephropathy in diabetes. A comprehensive literature review of observational studies on DKD published within the past ten years, with 57 percent published within the past three years was carried out. The article search focused on original research studies and reviews published in English. The articles were explored using Google Scholar, Medline, Web of Science, and PubMed databases based on keywords, titles, and abstracts related to the topic. This article provides a detailed relationship between hyperglycaemia, oxidative stress, and various cellular mechanisms that underlie the onset and progression of the disease. Moreover, it also shows how these mechanisms affect organelle dysfunction, resulting in fibrosis and podocyte impairment. The advances in understanding the complexity of DKD mechanisms discussed in this review will expedite opportunities to develop new interventions for treating the disease.

Background: Most existing risk equations for predicting/stratifying individual diabetic kidney disease (DKD) risks were developed using relatively dated data from selective and homogeneous trial populations comprising predominately Caucasian type 2 diabetes (T2D) patients. We seek to adapt risk equations for prediction of DKD progression (microalbuminuria, macroalbuminuria, and renal failure) using empiric data from a real-world population with T2D in Taiwan., Methods: Risk equations from three well-known simulation models: UKPDS-OM2, RECODe, and CHIME models, were adapted. Discrimination and calibration were determined using the area under the receiver operating characteristic curve (AUROC), a calibration plot (slope and intercept), and the Greenwood-Nam-D'Agostino (GND) test. Recalibration was performed for unsatisfactory calibration (p-value of GND test < 0.05) by adjusting the baseline hazards of risk equations to address risk variations among patients., Results: The RECODe equations for microalbuminuria and macroalbuminuria showed moderate discrimination (AUROC: 0.62 and 0.76) but underestimated the event risks (calibration slope > 1). The CHIME equation had the best discrimination for renal failure (AUROCs from CHIME, UKPDS-OM2 and RECODe: 0.77, 0.60 and 0.64, respectively). All three equations overestimated renal failure risk (calibration slope < 1). After rigorous updating, the calibration slope/intercept of the recalibrated RECODe for predicting microalbuminuria (0.87/0.0459) and macroalbuminuria (1.10/0.0004) risks as well as the recalibrated CHIME equation for predicting renal failure risk (0.95/-0.0014) were improved., Conclusions: Risk equations for prediction of DKD progression in real-world Taiwanese T2D patients were established, which can be incorporated into a multi-state simulation model to project and differentiate individual DKD risks for supporting timely interventions and health economic research., (© 2024. The Author(s).)

Background: Diabetic kidney disease (DKD) is the major complication of diabetes concomitant with gut dysbiosis and glycometabolic disorder, which are strongly associated with bile acid (BA) metabolism. Yet studies investigating the BA metabolism involving in DKD pathogenesis are limited. This study aimed to explore the metabolomic profiling of BAs in DKD and analyze its association with DKD progression., Methods: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to quantify BAs in the plasma, fecal and urine samples of patients with DKD or T2DM and healthy individuals (n = 30 for each group). The key BAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and receiver-operating characteristic (ROC) curve. Polynomial regression and Pearson's correlation analyses were performed to assess the correlation between the key BAs and the clinical indicators reflecting DKD progression., Results: Metabolomic profiling of 50 kinds of BAs presented the markedly step-wise alterations of BAs in plasma and feces as well as the little in urine of patients with DKD. Eight kinds of BAs in the plasma, eight kinds in the feces and three kinds in the urine were abnormally expressed, accompanying with the increased conjugated/unconjugated ratios of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid and hyocholic acid in the plasma, and of cholic acid, chenodeoxycholic acid and lithocholic acid in the feces. Moreover, the increased plasma level of glycochenodeoxycholic acid, and the increased fecal levels of glycolithocholic acid, 7-ketodeoxycholic acid and chenodeoxycholic acid-3-β-D-glucuronide are strongly correlated with the clinical indicators reflecting DKD progression, including eGFR, 24 h urinary protein and 24 h urinary microalbumin., Conclusions: Our study for the first time disclosed the specific alterations of BA metabolism reflecting the step-wise progression of DKD, providing the basis for early identification and therapeutical strategies for DKD., (© 2024. The Author(s).)

Background: Diabetic nephropathy (DN) has been a major factor in the outbreak of end-stage renal disease for decades. As the underlying mechanisms of DN development remains unclear, there is no ideal methods for the diagnosis and therapy., Objective: We aimed to explore the key genes and pathways that affect the rate progression of DN., Methods: Nanopore-based full-length transcriptome sequencing was performed with serum samples from DN patients with slow progression (DNSP, n = 5) and rapid progression (DNRP, n = 6)., Results: Here, transcriptome proclaimed 22,682 novel transcripts and obtained 45,808 simple sequence repeats, 1,815 transcription factors, 5,993 complete open reading frames, and 1,050 novel lncRNA from the novel transcripts. Moreover, a total of 341 differentially expressed transcripts (DETs) and 456 differentially expressed genes (DEGs) between the DNSP and DNRP groups were identified. Functional analyses showed that DETs mainly involved in ferroptosis-related pathways such as oxidative phosphorylation, iron ion binding, and mitophagy. Moreover, Functional analyses revealed that DEGs mainly involved in oxidative phosphorylation, lipid metabolism, ferroptosis, autophagy/mitophagy, apoptosis/necroptosis pathway., Conclusion: Collectively, our study provided a full-length transcriptome data source for the future DN research, and facilitate a deeper understanding of the molecular mechanisms underlying the differences in fast and slow progression of DN., (© 2024. The Author(s).)