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Valproic acid is an effective treatment for generalized seizure and related neurological defects. Despite its efficacy and acceptability, its use is associated with adverse drug effects. Moringa oleifera leaves are rich in phytochemical and nutritional components. It has excellent antioxidant and ethnobotanical benefits, thus popular among folk medicines and nutraceuticals. In the present study, 70% ethanol extract of moringa leaves was assessed for its in vivo biochemical and histological effects against valproate-induced kidney damage. Female Sprague-Dawley rats were randomly divided into four groups: Group I: control animals given physiological saline ( n = 8); Group II: Moringa extract-administered group (0.3 g/kg b.w./day, n = 8); Group III: valproate-administered animals (0.5 g/kg b.w./day, n = 15); and Group IV: valproate + moringa extract (given similar doses of both valproate and moringa extract, n = 12) administered group. Treatments were administered orally for 15 days, the animals were fasted overnight, anesthetized, and then tissue samples harvested. In the valproate-administered experimental group, serum urea and uric acid were elevated. In the kidney tissue of the valproate rats, glutathione was depleted, antioxidant enzyme activities (superoxide dismutase, catalase, glutathione reductase, glutathione S -transferase, and glutathione peroxidase) disrupted, while oxidative stress biomarker, inflammatory proteins (Tumor necrosis factor-alpha and interleukin-6), histological damage scores, and the number of PCNA-positive cells were elevated. M. oleifera attenuated all these biochemical defects through its plethora of diverse antioxidant and therapeutic properties.

The kidneys are life-sustaining organs that are vital to removing waste from our bodies. Because of their anatomic position and high blood flow, the kidneys are vulnerable to damage due to infections and autoinflammatory conditions. Even now, our knowledge of immune responses in the kidney is surprisingly rudimentary. Studying kidney-specific immune events is challenging because of the poor regenerative capacity of the nephrons, accumulation of uremic toxins, and hypoxia- and arterial blood pressure-mediated changes, all of which have unexpected positive or negative impacts on the immune response in the kidney. Kidney-specific defense confers protection against pathogens. On the other hand, unresolved inflammation leads to kidney damage and fibrosis. Interleukin-17 is a proinflammatory cytokine that has been linked to immunity against pathogens and pathogenesis of autoinflammatory diseases. In this review, we discuss current knowledge of IL-17 activities in the kidney in the context of infections, autoinflammatory diseases, and renal fibrosis.

Abstract: Prepubertal obesity is growing at an alarming rate and is now considered a risk factor for renal injury. Recently, we reported that the early development of renal injury in obese Dahl salt-sensitive (SS) leptin receptor mutant (SS LepR mutant) rats was associated with increased T-cell infiltration and activation before puberty. Therefore, the current study investigated the effect of inhibiting T-cell activation with abatacept on the progression of renal injury in young obese SS LepR mutant rats before puberty. Four-week-old SS and SS LepR mutant rats were treated with IgG or abatacept (1 mg/kg; ip, every other day) for 4 weeks. Abatacept reduced the renal infiltration of T cells by almost 50% in SS LepR mutant rats. Treatment with abatacept decreased the renal expression of macrophage inflammatory protein-3 alpha while increasing IL-4 in SS LepR mutant rats without affecting SS rats. While not having an impact on blood glucose levels, abatacept reduced hyperinsulinemia and plasma triglycerides in SS LepR mutant rats without affecting SS rats. We did not observe any differences in the mean arterial pressure among the groups. Proteinuria was markedly higher in SS LepR mutant rats than in SS rats throughout the study, and treatment with abatacept decreased proteinuria by about 40% in SS LepR mutant rats without affecting SS rats. We observed significant increases in glomerular and tubular injury and renal fibrosis in SS LepR mutant rats versus SS rats, and chronic treatment with abatacept significantly reduced these renal abnormalities in SS LepR mutant rats. These data suggest that renal T-cell activation contributes to the early progression of renal injury associated with prepubertal obesity., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In kidney damage, molecular changes can be used as early damage kidney biomarkers, such as Kidney Injury Molecule-1 and Neutrophil gelatinase-associated lipocalin. These biomarkers are associated with toxic metal exposure or disturbed homeostasis of trace elements, which might lead to serious health hazards. This study aimed to evaluate the relationship between exposure to trace elements and early damage kidney biomarkers in a pediatric population., Methods: In Tlaxcala, a cross-sectional study was conducted on 914 healthy individuals. The participants underwent a medical review and a socio-environmental questionnaire. Five early damage kidney biomarkers were determined in the urine with Luminex, and molybdenum, copper, selenium, nickel, and iodine were measured with ICP-Mass., Results: The eGFR showed a median of 103.75 mL/min/1.73 m2. The median levels for molybdenum, copper, selenium, nickel, and iodine were 24.73 ng/mL, 73.35 ng/mL, 4.78 ng/mL, 83.68 ng/mL, and 361.83 ng/mL, respectively. Except for molybdenum and nickel, the other trace elements had significant associations with the eGFR and the early kidney damage biomarkers. Additionally, we report the association of different exposure scenarios with renal parameters., Discussion: and Conclusions. Among the explored metals, exposure to Cu and iodine impairs renal function. In contrast, Se may manifest as a beneficial metal. Interactions of Mo-Se and Mo-Iodine seem to alter the expression of NGAL; Mo-Cu for CLU; Mo-Cu, Mo-Se, and Mo-iodine for Cys-C and a-1MG; and Mo-Cu and Mo-iodine for KIM-1; were noticed. Our study could suggest that trace element interactions were associated with early kidney damage biomarkers., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: To explore the molecular mechanism of Astragaloside IV (AS-IV) in alleviating renal fibrosis by inhibiting Urotensin II-induced pyroptosis and epithelial-mesenchymal transition of renal tubular epithelial cells., Methods: Forty SD rats were randomly divided into control group without operation: gavage with 5ml/kg/d water for injection and UUO model group: gavage with 5ml/kg/d water for injection; UUO+ AS-IV group (gavage with AS-IV 20mg/kg/d; and UUO+ losartan potassium group (gavage with losartan potassium 10.3mg/kg/d, with 10 rats in each group. After 2 weeks, Kidney pathology, serum Urotensin II, and cAMP concentration were detected, and the expressions of NLRP3, GSDMD-N, Caspase-1, and IL-1β were detected by immunohistochemistry. Rat renal tubular epithelial cells were cultured in vitro, and different concentrations of Urotensin II were used to intervene for 24h and 48h. Cell proliferation activity was detected using the CCK8 assay. Suitable concentrations of Urotensin II and intervention time were selected, and Urotensin II receptor antagonist (SB-611812), inhibitor of PKA(H-89), and AS-IV (15ug/ml) were simultaneously administered. After 24 hours, cells and cell supernatants from each group were collected. The cAMP concentration was detected using the ELISA kit, and the expression of PKA, α-SMA, FN, IL-1β, NLRP3, GSDMD-N, and Caspase-1 was detected using cell immunofluorescence, Western blotting, and RT-PCR., Results: Renal tissue of UUO rats showed renal interstitial infiltration, tubule dilation and atrophy, renal interstitial collagen fiber hyperplasia, and serum Urotensin II and cAMP concentrations were significantly higher than those in the sham operation group (p <0.05). AS-IV and losartan potassium intervention could alleviate renal pathological changes, and decrease serum Urotensin II, cAMP concentration levels, and the expressions of NLRP3, GSDMD-N, Caspase-1, and IL-1β in renal tissues (p <0.05). Urotensin II at a concentration of 10-8 mol/L could lead to the decrease of cell proliferation, (p<0.05). Compared with the normal group, the cAMP level and the PKA expression were significantly increased (p<0.05). After intervention with AS-IV and Urotensin II receptor antagonist, the cAMP level and the expression of PKA were remarkably decreased (p<0.05). Compared with the normal group, the expression of IL-1β, NLRP3, GSDMD-N, and Caspase-1 in the Urotensin II group was increased (p<0.05), which decreased in the AS-IV and H-89 groups., Conclusion: AS-IV can alleviate renal fibrosis by inhibiting Urotensin II-induced pyroptosis of renal tubular epithelial cells by regulating the cAMP/PKA signaling pathway., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang 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.)

Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding to acylated proteins. These characteristics lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, ultimately resulting in cell death. Cuproptosis is distinct from other types of cell death, including necrosis, apoptosis, ferroptosis, and pyroptosis. Cu induces oxidative stress damage, protein acylation, and the oligomerization of acylated TCA cycle proteins. These processes lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, disrupting cellular Cu homeostasis, and causing cell death. Cuproptosis plays a significant role in the development and progression of various kidney diseases such as acute kidney injury, chronic kidney disease, diabetic nephropathy, kidney transplantation, and kidney stones. On the one hand, inducers of cuproptosis, such as disulfiram (DSF), chloroquinolone, and elesclomol facilitate cuproptosis by promoting cell oxidative stress. In contrast, inhibitors of Cu chelators, such as tetraethylenepentamine and tetrathiomolybdate, relieve these diseases by inhibiting apoptosis. To summarize, cuproptosis plays a significant role in the pathogenesis of kidney disease. This review comprehensively discusses the molecular mechanisms underlying cuproptosis and its significance in kidney diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Opisthorchis viverrini (O. viverrini, Ov) infection and consumption of high-fat and high-fructose (HFF) diet exacerbate liver and kidney disease. Here, we investigated the effects of a combination of O. viverrini infection and HFF diet on kidney pathology via changes in the gut microbiome and host proteome in hamsters., Methodology/principal Findings: Twenty animals were divided into four groups; 1) fed a normal diet not infected with O. viverrini (normal group), 2) fed an HFF diet and not infected with O. viverrini (HFF), 3) fed a normal diet and infected with O. viverrini (Ov), and 4) fed an HFF diet and infected with O. viverrini (HFFOv). DNA was extracted from fecal samples and the V3-V4 region of the bacterial 16S rRNA gene sequenced on an Illumina MiSeq sequencing platform. In addition, LC/MS-MS analysis was done. Histopathological studies and biochemical assays were also conducted. The results indicated that the HFFOv group exhibited the most severe kidney injury, manifested as elevated KIM-1 expression and accumulation of fibrosis in kidney tissue. The microbiome of the HFFOv group was more diverse than in the HFF group: there were increased numbers of Ruminococcaceae, Lachnospiraceae, Desulfovibrionaceae and Akkermansiaceae, but fewer Eggerthellaceae. In total, 243 host proteins were identified across all groups. Analysis using STITCH predicted that host proteome changes may lead to leaking of the gut, allowing molecules such as soluble CD14 and p-cresol to pass through to promote kidney disease. In addition, differential expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (Tab2, involving renal inflammation and injury) are predicted to be associated with kidney disease., Conclusions/significance: The combination of HFF diet and O. viverrini infection may promote kidney injury through alterations in the gut microbiome and host proteome. This knowledge may suggest an effective strategy to prevent kidney disease beyond the early stages., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tunbenjasiri 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.)

These last years, the growth factor GDF15 has emerged as a key element in many different biological processes. It has been established as being produced in response to many pathological states and is now referred to as a stress-related hormone. Regarding kidney functions, GDF15 has been involved in different pathologies such as chronic kidney disease, diabetic nephropathy, renal cancer, and so on. Interestingly, recent studies also revealed a role of GDF15 in the renal homeostatic mechanisms allowing to maintain constant, as far as possible, the plasma parameters such as pH and K + values. In this review, we recapitulate the role of GDF15 in physiological and pathological context by focusing our interest on its renal effect.

In this study, we aimed to investigate the protective effects of Panax notoginseng and leech (PL) on renal fibrosis and explore the mechanisms underlying their actions. For this study, we created an adenine-induced renal fibrosis model in SD rats to investigate the protective effect of PL on renal fibrosis and explore its underlying mechanism. Initially, we assessed the renal function in RF rats and found that Scr, BUN, and urine protein content decreased after PL treatment, indicating the protective effect of PL on renal function. Histological analysis using HE and Masson staining revealed that PL reduced inflammatory cell infiltration and decreased collagen fiber deposition in renal tissue. Subsequently, we analyzed the levels of α-SMA, Col-IV, and FN, which are the main components of the extracellular matrix (ECM), using IHC, RT-qPCR, and WB. The results demonstrated that PL was effective in reducing the accumulation of ECM, with PL1-2 showing the highest effectiveness. To further understand the underlying mechanisms, we conducted UPLC-MS/MS analysis on the incoming components of the PL1-2 group. The results revealed several associations between the differential components and antioxidant and mitochondrial functions. This was further confirmed by enzyme-linked immunosorbent assay and biochemical indexes, which showed that PL1-2 ameliorated oxidative stress by reducing ROS and MDA production and increasing GSH and SOD levels. Additionally, transmission electron microscopy results indicated that PL1-2 promoted partial recovery of mitochondrial morphology and cristae. Finally, using RT-qPCR and WB, an increase in the expression of mitochondrial fusion proteins Mfn1, Mfn2, and Opa1 after PL1-2 treatment was observed, coupled with a decline in the expression and phosphorylation of mitochondrial cleavage proteins Fis and Drp1. These findings collectively demonstrate that PL1-2 ameliorates renal fibrosis by reducing oxidative stress and restoring mitochondrial balance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen 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.)

Natriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by binding to natriuretic peptide receptors 1 and 2 (NPR1/2), whereas natriuretic peptide receptor 3 (NPR3) acts as a clearance receptor that removes NPs from the circulation. Mouse studies have shown that local NP-signaling in the kidney glomerulus is important for the maintenance of renal homeostasis. In this study we examined the expression of NPR3 in kidney tissue and explored its involvement in renal physiology and disease by generating podocyte-specific knockout mice (NPR3 podKO ) as well as by using an NPR3 inhibitor (NPR3i) in rodent models of kidney disease. NPR3 was highly expressed by podocytes. NPR3 podKO animals showed no renal abnormalities under healthy conditions and responded similarly to nephrotoxic serum (NTS) induced glomerular injury. However, NPR3i showed reno-protective effects in the NTS-induced model evidenced by decreased glomerulosclerosis and reduced podocyte loss. In a ZSF1 rat model of diabetic kidney injury, therapy alone with NPR3i did not have beneficial effects on renal function/histology, but when combined with losartan (angiotensin receptor blocker), NPR3i potentiated its ameliorative effects on albuminuria. In conclusion, these results suggest that NPR3 may contribute to kidney disease progression., (© 2024. The Author(s).)

Renal interstitial fibrosis (RIF) is a classic pathophysiological process of chronic kidney disease (CKD). However, the mechanisms underlying RIF remain unclear. The present study found that a novel circular RNA, cirInpp5b, might be involved in RIF by high-throughput sequencing. Subsequent experiments revealed that circInpp5b was reduced in UUO mouse kidney tissues and TGF-β1-treated proximal tubular cells. The overexpression of circInpp5b inhibited RIF in UUO mice and prevented extracellular matrix (ECM) deposition in TGF-β1-treated proximal tubular cells. Furthermore, overexpression of circInpp5b down-regulated the protein level of DDX1. Mechanistically, circInpp5b bound to the DDX1 protein and promoted its lysosomal degradation. Collectively, the findings of our study demonstrate that circInpp5b ameliorates RIF by binding to the DDX1 protein and promoting its lysosomal degradation.

Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.

Uncovering the function of understudied G protein-coupled receptors (GPCRs) provides a wealth of untapped therapeutic potential. The poorly understood adhesion GPCR Gpr126 ( Adgrg6 ) is widely expressed in developing kidneys. In adulthood, Gpr126 expression is enriched in parietal epithelial cells (PECs) and epithelial cells of the collecting duct and urothelium. Whether Gpr126 plays a role in kidney disease remains unclear. Here, we characterized Gpr126 expression in diseased kidneys in mice, rats, and humans. RT-PCR data show that Gpr126 expression is altered in kidney disease. A quantitative RNAscope ® analysis utilizing cell type-specific markers revealed that Gpr126 expression upon tubular damage is mainly increased in cell types expressing Gpr126 under healthy conditions as well as in cells of the distal and proximal tubules. Upon glomerular damage, an increase was mainly detected in PECs. Notably, Gpr126 expression was upregulated in an ischemia/reperfusion model within hours, while upregulation in a glomerular damage model was only detected after weeks. An analysis of kidney microarray data from patients with lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), hypertension, and diabetes as well as single-cell RNA-seq data from kidneys of patients with acute kidney injury and chronic kidney disease indicates that GPR126 expression is also altered in human kidney disease. In patients with FSGS, an RNAscope ® analysis showed that GPR126 mRNA is upregulated in PECs belonging to FSGS lesions and proximal tubules. Collectively, we provide detailed insights into Gpr126 expression in kidney disease, indicating that GPR126 is a potential therapeutic target.

Chronic kidney disease (CKD) is a disorder that causes changes in both the structure and function of the kidneys, causing complications such as hypertension, edema, and oliguria. Renal fibrosis is also a common pathological feature of CKD. Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix (ECM) proteins. The proteinase domain consists of a zinc ion in the active site, which contributes to its stabilization with another zinc and three calcium structural ions. Many cellular processes are controlled by MMPs, such as cell-cell interactions and various signaling pathways, while they are also involved in degrading substrates on cell surfaces. Tissue inhibitors of metalloproteinases (TIMPs) are key regulators of metalloproteinases, and both are involved in regulating cell turnover, the regulation, and the progression of fibrosis and apoptosis in the tissue. MMPs play a role in renal fibrosis, such as the tubular cell epithelial-mesenchymal transition (TEM), activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT), and pericyte-myofibroblast transdifferentiation. This review aims to show the mechanisms through which MMPs contribute to renal fibrosis, paying particular attention to MMP-9 and the epithelial-mesenchymal transition., Competing Interests: The authors declare no conflict of interest. Raffaele Serra is serving as one of the Editorial Board members of this journal. We declare that Raffaele Serra had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Amancio Carnero Moya., (© 2024 The Author(s). Published by IMR Press.)

Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 μM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins., 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.)

MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-β (PDGFR-β)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-β. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-β. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p., (© 2024. The Author(s).)

Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-β1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-β1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3'UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF.

Early detection of drug-induced kidney injury is essential for drug development. In this study, multiple low-dose aristolochic acid (AA) and cisplatin (Cis) injections increased renal mRNA levels of inflammation, fibrosis, and renal tubule injury markers. We applied a serum amyloid A3 (Saa3) promoter-driven luciferase reporter (Saa3 promoter-luc mice) to these two tubulointerstitial nephritis models and performed in vivo bioluminescence imaging to monitor early renal pathologies. The bioluminescent signals from renal tissues with AA or CIS injections were stronger than those from normal kidney tissues obtained from normal mice. To verify whether the visualized bioluminescence signal was specifically generated by the injured kidney, we performed in vivo bioluminescence analysis after opening the stomachs of Saa3 promoter-luc mice, and the Saa3-mediated bioluminescent signal was specifically detected in the injured kidney. This study showed that Saa3 promoter activity is a potent non-invasive indicator for the early detection of drug-induced nephrotoxicity., Competing Interests: The authors declare no conflicts of interest.

Numerous myofibroblasts are arisen from endothelial cells (ECs) through endothelial to mesenchymal transition (EndMT) triggered by TGF-β. However, the mechanism of ECs transforms to a different subtype, or whether there exists an intermediate state of ECs remains unclear. In present study, we demonstrate Midkine (MDK) mainly expressed by CD31 + ACTA2+ECs going through partial EndMT contribute greatly to myofibroblasts by spatial and single-cell transcriptomics. MDK is induced in TGF-β treated ECs, which upregulates C/EBPβ and increases EndMT genes, and these effects could be reversed by siMDK. Mechanistically, MDK promotes the binding ability of C/EBPβ with ACTA2 promoter by stabilizing the C/EBPβ protein. In vivo, knockout of Mdk or conditional knockout of Mdk in ECs reduces EndMT markers and significantly reverses fibrogenesis. In conclusion, our study provides a mechanistic link between the induction of EndMT by TGF-β and MDK, which suggests that blocking MDK provides potential therapeutic strategies for renal fibrosis., (© 2024. The Author(s).)

Abstract: Over the past decade, mitochondrial dysfunction has been investigated as a key contributor to acute and chronic kidney disease. However, the precise molecular mechanisms linking mitochondrial damage to kidney disease remain elusive. The recent insights into the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthetase (cGAS)-stimulator of interferon gene (STING) signaling pathway have revealed its involvement in many renal diseases. One of these findings is that mitochondrial DNA (mtDNA) induces inflammatory responses via the cGAS-STING pathway. Herein, we provide an overview of the mechanisms underlying mtDNA release following mitochondrial damage, focusing specifically on the association between mtDNA release-activated cGAS-STING signaling and the development of kidney diseases. Furthermore, we summarize the latest findings of cGAS-STING signaling pathway in cell, with a particular emphasis on its downstream signaling related to kidney diseases. This review intends to enhance our understanding of the intricate relationship among the cGAS-STING pathway, kidney diseases, and mitochondrial dysfunction., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Sirtuin3 (SIRT3), a mitochondrial deacetylase, has been shown to be involved in various kidney diseases. In this study, we aimed to clarify the role of SIRT3 in cyclosporine-induced nephrotoxicity and the associated mitochondrial dysfunction. Madin-Darby canine kidney (MDCK) cells were transfected with Flag-tagged SIRT3 for SIRT3 overexpression or SIRT3 siRNA for the inhibition of SIRT3. Subsequently, the cells were treated with cyclosporine A (CsA) or vehicle. Wild-type and SIRT3 knockout (KO) mice were randomly assigned to receive cyclosporine A or olive oil. Furthermore, SIRT3 activator, honokiol, was treated alongside CsA to wild type mice. Our results revealed that CsA treatment inhibited mitochondrial SIRT3 expression in MDCK cells. Inhibition of SIRT3 through siRNA transfection exacerbated apoptosis, impaired the expression of the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK-PGC1α) pathway, and worsened mitochondrial dysfunction induced by CsA treatment. Conversely, overexpression of SIRT3 through Flag-tagged SIRT3 transfection ameliorated apoptosis, increased the expression of mitochondrial superoxide dismutase 2, and restored the mitochondrial regulator pathway, AMPK-PGC1α. In SIRT3 KO mice, CsA treatment led to aggravated kidney dysfunction, increased kidney tubular injury, and accumulation of oxidative end products indicative of oxidative stress injury. Meanwhile, SIRT3 activation in vivo significantly mitigated these adverse effects, improving kidney function, reducing oxidative stress markers, and enhancing mitochondrial health following CsA treatment. Overall, our findings suggest that SIRT3 plays a protective role in alleviating mitochondrial dysfunction caused by CsA through the activation of the AMPK-PGC1α pathway, thereby preventing further kidney injury., (© 2024. The Author(s).)

Background: Long-term exposure to cadmium can induce renal toxicity in rats, leading to endoplasmic reticulum (ER) stress and iron death. Notably, in cadmium-exposed rats, there is an increased expression of UNC93B1 (unc-93 homolog B1). Consequently, our investigation aims to determine the impact of UNC93B1 on ER stress and iron death in cadmium-exposed rats by modulating the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway., Methods: A cadmium-exposed rat model was established by intrabacally injecting chromium chloride (5 mg/kg, once a day for 4 weeks), and the levels of UCd (urine cadmium), UNAG (urine N -acetyl-β-D-glucosaminidase), and UCr (urine creatinine) in urine were assessed. A silent UNC93B1 lentivirus was constructed, and STING agonists were procured and administered to the rats. Subsequently, kidney tissues were extracted post-mortem, and pathological changes in renal tissue were observed through hematoxylin and eosin (HE) staining. The expression and mRNA levels of UNC93B1, cGAS, and STING were examined using western blot (WB) and polymerase chain reaction (PCR). Autophagy proteins (light chain 3 (LC3), Beclin-1, p62) were also assessed by WB. Additionally, iron concentration was determined using a kit, while oxidative stress markers (cytochrome oxidase subunit 2 (COX2), glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH)) were measured through enzyme-linked immunosorbent assay (ELISA). Furthermore, endoplasmic reticulum stress proteins (protein kinase RNA-like ER kinase (PERK), CCAAT enhance-binding protein homologous protein (CHOP), activating transcription factor-4 (ATF4)) were analyzed by WB., Results: Wstaining, WB, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), ELISA, and HE staining collectively revealed a heightened expression of UNC93B1, cGAS, and STING, accompanied by increased levels of autophagy, oxidative stress, and ER stress in cadmium-exposed rats ( p < 0.05). Nephrotoxicity exhibited a reduction following the inhibition of UNC93B1, leading to decreased levels of oxidative stress, autophagy, and ER stress ( p < 0.05). Notably, this observed phenomenon was reversed upon the addition of STING agonists, suggesting that UNC93B1 might exert a nephroprotective effect in cadmium-exposed rats through modulation of the cGAS-STING pathway., Conclusions: The inhibition of UNC93B1 mitigates nephrotoxicity in cadmium-exposed rats, and this protective effect is mechanistically linked to the cGAS-STING pathway.

Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and the unfolded protein response, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the cross talk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondria-related clinical research.

PAX2 regulates kidney development, and its expression persists in parietal epithelial cells (PECs), potentially serving as a podocyte reserve. We hypothesized that mice with a Pax2 pathogenic missense variant ( Pax2 A220G/+ ) have impaired PEC-mediated podocyte regeneration. Embryonic wild-type mouse kidneys showed overlapping expression of PAX2/Wilms' tumor-1 (WT-1) until PEC and podocyte differentiation, reflecting a close lineage relationship. Embryonic and adult Pax2 A220G/+ mice have reduced nephron number but demonstrated no glomerular disease under baseline conditions. Pax2 A220G/+ mice compared with wild-type mice were more susceptible to glomerular disease after adriamycin (ADR)-induced podocyte injury, as demonstrated by worsened glomerular scarring, increased podocyte foot process effacement, and podocyte loss. There was a decrease in PAX2-expressing PECs in wild-type mice after adriamycin injury accompanied by the occurrence of PAX2/WT-1-coexpressing glomerular tuft cells. In contrast, Pax2 A220G/+ mice showed no changes in the numbers of PAX2-expressing PECs after adriamycin injury, associated with fewer PAX2/WT-1-coexpressing glomerular tuft cells compared with injured wild-type mice. A subset of PAX2-expressing glomerular tuft cells after adriamycin injury was increased in Pax2 A220G/+ mice, suggesting a pathological process given the worse outcomes observed in this group. Finally, Pax2 A220G/+ mice have increased numbers of glomerular tuft cells expressing Ki-67 and cleaved caspase-3 compared with wild-type mice after adriamycin injury, consistent with maladaptive responses to podocyte loss. Collectively, our results suggest that decreased glomerular numbers in Pax2 A220G/+ mice are likely compounded with the inability of their mutated PECs to regenerate podocyte loss, and together these two mechanisms drive the worsened focal segmental glomerular sclerosis phenotype in these mice. NEW & NOTEWORTHY Congenital anomalies of the kidney and urinary tract comprise some of the leading causes of kidney failure in children, but our previous study showed that one of its genetic causes, PAX2 , is also associated with adult-onset focal segmental glomerular sclerosis. Using a clinically relevant model, our present study demonstrated that after podocyte injury, parietal epithelial cells expressing PAX2 are deployed into the glomerular tuft to assist in repair in wild-type mice, but this mechanism is impaired in Pax2 A220G/+ mice.

Background and Purpose: Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent aristolochic acid nephropathy. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent aristolochic acid nephropathy and determined the underlying mechanism., Experimental Approach: HDACs expression in the aristolochic acid nephropathy model was examined. The activation of PANoptosis of mouse kidney and renal tubular epithelial cell were assessed after exposure to HDAC1 and HDAC2 blockade. Kidney-specific knock-in of proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) mice were used to investigate whether PSTPIP2 affected the production of PANoptosome., Key Results: Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and HDAC2 specific inhibitor, romidepsin (FK228, depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against aristolochic acid nephropathy. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knock-in mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mouse renal tubular epithelial cells (mTECs). Additionally, PSTPIP2 was found to regulate caspase 8 in aristolochic acid nephropathy., Conclusion and Implications: HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and HDAC2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for preventing aristolochic acid nephropathy., (© 2023 British Pharmacological Society.)

Sirtuins (SIRTs) are putative regulators of lifespan in model organisms. Since the initial discovery that SIRTs could promote longevity in nematodes and flies, the identification of additional properties of these proteins has led to understanding of their roles as exquisite sensors that link metabolic activity to oxidative states. SIRTs have major roles in biological processes that are important in kidney development and physiological functions, including mitochondrial metabolism, oxidative stress, autophagy, DNA repair and inflammation. Furthermore, altered SIRT activity has been implicated in the pathophysiology and progression of acute and chronic kidney diseases, including acute kidney injury, diabetic kidney disease, chronic kidney disease, polycystic kidney disease, autoimmune diseases and renal ageing. The renoprotective roles of SIRTs in these diseases make them attractive therapeutic targets. A number of SIRT-activating compounds have shown beneficial effects in kidney disease models; however, further research is needed to identify novel SIRT-targeting strategies with the potential to treat and/or prevent the progression of kidney diseases and increase the average human healthspan., (© 2024. Springer Nature Limited.)

Introduction: Shenqi pill (SQP) can be used to treat various kidney related diseases, but its exact mechanism of action remains unclear. We intended to analyze the role and mechanism of SQP on renal interstitial fibrosis (RIF)., Methods: After performing unilateral ureteral obstruction (UUO) surgery following the Institutional Animal Care and Use Committee guidelines, all rats were assigned into the sham group, UUO group, UUO + SQP 1.5 g/kg, UUO + SQP 3 g/kg, and UUO + SQP 6 g/kg groups. After treatment with SQP for 4 weeks, the appearance of kidney, serum creatinine (SCr), and blood urea nitrogen (BUN) levels were monitored in each group. The pathological injury, extracellular matrix (ECM), and Notch1 pathway-related protein levels were measured using H&E staining, Masson staining, immunohistochemistry, and Western blot, respectively., Results: SQP could obviously ameliorate the appearance of the kidney as well as the levels of SCr and BUN in UUO rats (SCr: 67.6 ± 4.64 μM, 59.66 ± 4.96 μM, 48.76 ± 4.44 μM, 40.43 ± 3.02 μM for UUO, low, medium, and high SQP treatment groups; BUN: 9.09 ± 0.97 mM, 7.72 ± 0.61 mM, 5.42 ± 0.42 mM, 4.24 ± 0.34 mM for UUO, low, medium, and high SQP treatment groups; P < .05). SQP also effectively mitigated renal tissue injury in UUO rats (P < .05). Moreover, we uncovered that SQP significantly inhibited Collagen I, α-SMA, Collagen IV, TGF-B1, Notch1, and Jag1 protein expressions in UUO rats kidney (P < .05)., Conclusion: Our data elucidated that SQP can alleviate RIF, and the mechanism may be related to the Notch1/Jag1 pathway. DOI: 10.52547/ijkd.7703.

The pathological features of acute and chronic kidney diseases are closely associated with cell death in glomeruli and tubules. Ferroptosis is a form of programmed cell death characterized by iron overload-induced oxidative stress. Ferroptosis has recently gained increasing attention as a pathogenic mechanism of kidney damage. Specifically, the ferroptosis signaling pathway has been found to be involved in the pathological process of acute and chronic kidney injury, potentially contributing to the development of both acute and chronic kidney diseases. This paper aims to elucidate the underlying mechanisms of ferroptosis and its role in the pathogenesis of kidney disease, highlighting its significance and proposing novel directions for its treatment., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The kidney is exposed to various mechanical stimuli and stress, yet little is known about kidney desmosomes. In healthy kidneys, we found desmosomal proteins located at the apical-junctional complex in tubular epithelial cells. In four different animal models and patient biopsies with various kidney diseases, desmosomal components were significantly upregulated and partly miss-localized outside of the apical-junctional complexes along the whole lateral tubular epithelial cell membrane. The most upregulated component was desmoglein-2 (Dsg2). Mice with constitutive tubular epithelial cell-specific deletion of Dsg2 developed normally, and other desmosomal components were not altered in these mice. When challenged with different types of tubular epithelial cell injury (unilateral ureteral obstruction, ischemia-reperfusion, and 2,8-dihydroxyadenine crystal nephropathy), we found increased tubular epithelial cell apoptosis, proliferation, tubular atrophy, and inflammation compared to wild-type mice in all models and time points. In vitro, silencing DSG2 via siRNA weakened cell-cell adhesion in HK-2 cells and increased cell death. Thus, our data show a prominent upregulation of desmosomal components in tubular cells across species and diseases and suggest a protective role of Dsg2 against various injurious stimuli., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Resveratrol (Res) has been demonstrated to have beneficial effects on gouty nephropathy (GN). However, the mechanisms of Res on GN remain unclear. This study aimed to investigate the mechanisms of Res on GN. In this study, network pharmacology technology was used to predict the Res targets in the prevention and treatment of GN. Renal metabonomics was used to identify differential metabolites in kidney tissue of GN model rats. Finally, molecular docking technology was used to verify the binding ability of Res to key targets. Metabonomics analysis showed that 24 potentially important metabolites were involved in the prevention and treatment of GN with Res. After exposure to Res, metabolite levels normalized. The network pharmacology analysis showed that 24 key targets were involved in the prevention and treatment of GN disease. According to the metabolite-gene network diagram, we identified two core genes, PTGS1 and PTGS2, and found that both were involved in the arachidonic acid metabolism pathway. Molecular docking further verified the affinity of Res binding to PTGS1 and PTGS2. In conclusion, the mechanism of Res against GN may be the regulation of arachidonic acid metabolism through the regulation of PTGS 1 and PTGS 2., (© 2024 John Wiley & Sons Ltd.)

Serotonin, while conventionally recognized as a neurotransmitter in the CNS, has recently gained attention for its role in the kidney. Specifically, serotonin is not only synthesized in the kidney, but it also regulates glomerular function, vascular resistance, and mitochondrial homeostasis. Because of serotonin's importance to mitochondrial health, this review is focused on the role of serotonin and its receptors in mitochondrial function in the context of acute kidney injury, chronic kidney disease, and diabetic kidney disease, all of which are characterized by mitochondrial dysfunction and none of which has approved pharmacological treatments. Evidence indicates that activation of certain serotonin receptors can stimulate mitochondrial biogenesis (MB) and restore mitochondrial homeostasis, resulting in improved renal function. Serotonin receptor agonists that induce MB are therefore of interest as potential therapeutic strategies for renal injury and disease. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is associated with many human renal diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease, which are associated with increased morbidity and mortality. Unfortunately, none of these pathologies has an FDA-approved pharmacological intervention, underscoring the urgency of identifying new therapeutics for such disorders. Studies show that induction of mitochondrial biogenesis via serotonin (5-hydroxytryptamine, 5-HT) receptors reduces kidney injury markers, restores mitochondrial and renal function after kidney injury, and decreases mortality, suggesting that targeting 5-HT receptors may be a promising therapeutic avenue for mitochondrial dysfunction in kidney diseases. While numerous reviews describe the importance of mitochondria and mitochondrial quality control mechanisms in kidney disease, the relevance of 5-HT receptor-mediated mitochondrial metabolic modulation in the kidney has yet to be thoroughly explored., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Ltd.)

Renal fibrosis is a typical pathological change in chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) is the predominant stage. Activation of macroautophagy/autophagy plays a crucial role in the process of EMT. Lycopene (LYC) is a highly antioxidant carotenoid with pharmacological effects such as anti-inflammation, anti-apoptosis and mediation of autophagy. In this study, we demonstrated the specific mechanism of LYC in activating mitophagy and improving renal fibrosis. The enrichment analysis results of GO and KEGG showed that LYC had high enrichment values with autophagy. In this study, we showed that LYC alleviated aristolochic acid I (AAI)-induced intracellular expression of PINK1, TGFB/TGF-β, p-SMAD2, p-SMAD3, and PRKN/Parkin, recruited expression of MAP1LC3/LC3-II and SQSTM1/p62, decreased mitochondrial membrane potential (MMP), and ameliorated renal fibrosis in mice. When we simultaneously intervened NRK52E cells using bafilomycin A 1 (Baf-A1), AAI, and LYC, intracellular MAP1LC3-II and SQSTM1 expression was significantly increased. A similar result was seen in renal tissue and cells when treated in vitro and in vivo with CQ, AAI, and LYC, and the inhibitory effect of LYC on the AAI-activated SMAD2-SMAD3 signaling pathway was attenuated. Molecular docking simulation experiments showed that LYC stably bound to the AKT active site. After intervention of cells with AAI and GSK-690693, the expression of PINK1, PRKN, MAP1LC3-II, BECN1, p-SMAD2 and p-SMAD3 was increased, and the expression of SQSTM1 was decreased. However, SC79 inhibited autophagy and reversed the inhibitory effect of LYC on EMT. The results showed that LYC could inhibit the AKT signaling pathway to activate mitophagy and reduce renal fibrosis. Abbreviation: AA: aristolochic acid; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB: actin beta; AKT/protein kinase B: thymoma viral proto-oncogene; BAF-A1: bafilomycin A 1 ; BECN1: beclin 1, autophagy related; CCN2/CTGF: cellular communication network factor 2; CDH1/E-Cadherin: cadherin 1; CKD: chronic kidney disease; COL1: collagen, type I; COL3: collagen, type III; CQ: chloroquine; ECM: extracellular matrix; EMT: epithelial-mesenchymal transition; FN1: fibronectin 1; LYC: lycopene; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase ; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PPI: protein-protein interaction; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1/p62: sequestosome 1; TGFB/TGFβ: transforming growth factor, beta; VIM: vimentin.

Kidney fibrosis is a common outcome of a wide variety of chronic kidney diseases, in which virtually all kinds of renal resident and infiltrating cells are involved. As such, well-orchestrated intercellular communication is of vital importance in coordinating complex actions during renal fibrogenesis. Cell-cell communication in multicellular organisms is traditionally assumed to be mediated by direct cell contact or soluble factors, including growth factors, cytokines and chemokines, through autocrine, paracrine, endocrine and juxtacrine signaling mechanisms. Growing evidence also demonstrates that extracellular vesicles, lipid bilayer-encircled particles naturally released from almost all types of cells, can act as a vehicle to transfer a diverse array of biomolecules including proteins, mRNA, miRNA and lipids to mediate cell-cell communication. We recently described a new mode of intercellular communication via building a special extracellular niche by insoluble matricellular proteins. Kidney cells, upon injury, produce and secrete different matricellular proteins, which incorporate into the local extracellular matrix network, and regulate the behavior, trajectory and fate of neighboring cells in a spatially confined fashion. This extracellular niche-mediated cell-cell communication is unique in that it restrains the crosstalk between cells within a particular locality. Detailed delineation of this unique manner of intercellular communication will help to elucidate the mechanism of kidney fibrosis and could offer novel insights in developing therapeutic intervention., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Fibrotic diseases are characterized by the uncontrolled accumulation of extracellular matrix (ECM) components leading to disruption of tissue homeostasis. Myofibroblasts as the main ECM-producing cells can originate from various differentiated cell types after injury. Particularly, the process of endothelial-to-mesenchymal transition (endMT), describing phenotypic shifts of endothelial cells to adopt a fully mesenchymal identity, may contribute to the pool of myofibroblasts in fibrosis, while leading to capillary rarefaction and exacerbation of tissue hypoxia. In renal disease, incomplete recovery from acute kidney injury (AKI) and the ensuing fibrotic reaction stand out as major contributors to chronic kidney disease (CKD) development. While the focus has largely been on impaired tubular epithelial repair as a potential fibrosis-driving mechanism, alterations in the renal microcirculation post-AKI, and in particular endMT as a maladaptive response, could hold equal significance. Dysfunctional interplays among various cell types in the kidney microenvironment can instigate endMT. Transforming growth factor beta (TGF-β) signaling, with its downstream activation of canonical/Smad-mediated and non-canonical pathways, has been identified as primary driver of this process. However, non-TGF-β-mediated pathways involving inflammatory agents and metabolic shifts in intercellular communication within the tissue microenvironment can also trigger endMT. These harmful, maladaptive cell-cell interactions and signaling pathways offer potential targets for therapeutic intervention to impede endMT and decelerate fibrogenesis such as in AKI-CKD progression. Presently, partial reduction of TGF-β signaling using anti-diabetic drugs or statins may hold therapeutic potential in renal context. Nevertheless, further investigation is warranted to validate underlying mechanisms and assess positive effects within a clinical framework., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

This study explores olive flounder by-product Prozyme2000P (OFBP) hydrolysate as a potential treatment for age-related kidney decline. Ferroptosis, a form of cell death linked to iron overload and oxidative stress, is increasingly implicated in aging kidneys. We investigated whether OFBP could inhibit ferroptosis and improve kidney health. Using TCMK-1 cells, we found that OFBP treatment protected cells from ferroptosis induced by sodium iodate (SI). OFBP also preserved the mitochondria health and influenced molecules involved in ferroptosis regulation. In aging mice, oral administration of OFBP significantly improved kidney health markers. Microscopic examination revealed reduced thickening and scarring in the kidney's filtering units, a hallmark of aging. These findings suggest that OFBP hydrolysate may be a promising therapeutic candidate for age-related kidney decline. By inhibiting ferroptosis, OFBP treatment appears to improve both cellular and structural markers of kidney health. Further research is needed to understand how OFBP works fully and test its effectiveness in more complex models.

Early life exposure lays the groundwork for the risk of developing cardiovascular-kidney-metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future.

Ochratoxin A (OTA), commonly found in various foods, significantly impacts the health of humans and animals, especially their kidneys. Our study explores OTA's effects on the gut microbiota and kidney damage while examining how postbiotics offer protection. Using metagenomic sequencing, we observed that OTA increased the potential gut pathogens such as Alistipes , elevating detrimental metabolites and inflammation. Also, OTA inhibited the Nrf2/HO-1 pathway, reducing kidney ROS elimination and leading to cellular ferroptosis and subsequent kidney damage. Postbiotics mitigate OTA's effects by downregulating the abundance of the assimilatory sulfate reduction IV pathway and virulence factors associated with iron uptake and relieving the inhibition of OTA on Nrf2/HO-1, restoring ROS-clearing capabilities and thereby alleviating chronic OTA-induced kidney damage. Understanding the OTA-gut-kidney link provides new approaches for preventing kidney damage, with postbiotics showing promise as a preventive treatment.

Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix and progressive loss of nephron function, with a lack of effective treatment options in clinical practice. In this study, we discovered that the Beclin-1-derived peptide MP1 significantly inhibits the abnormal expression of fibrosis and epithelial-mesenchymal transition-related markers, including α -smooth muscle actin, fibronectin, collagen I, matrix metallopeptidase 2, Snail1, and vimentin both in vitro and in vivo. H&E staining was employed to evaluate renal function, while serum creatinine (Scr) and blood urea nitrogen (BUN) were used as main indices to assess pathologic changes in the obstructed kidney. The results demonstrated that daily treatment with MP1 during the 14-day experiment significantly alleviated renal dysfunction and changes in Scr and BUN in mice with unilateral ureteral obstruction. Mechanistic research revealed that MP1 was found to have a significant inhibitory effect on the expression of crucial components involved in both the Wnt/ β -catenin and transforming growth factor (TGF)- β /Smad pathways, including β -catenin, C-Myc, cyclin D1, TGF- β 1, and p-Smad/Smad. However, MP1 exhibited no significant impact on either the LC3II/LC3I ratio or P62 levels. These findings indicate that MP1 improves renal physiologic function and mitigates the fibrosis progression by inhibiting the Wnt/ β -catenin pathway. Our study suggests that MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis. SIGNIFICANCE STATEMENT: This study indicated that the Beclin-1-derived peptide MP1 effectively mitigated renal fibrosis induced by unilateral ureteral obstruction through inhibiting the Wnt/β-catenin pathway and transforming growth factor-β/Smad pathway, thereby improving renal physiological function. Importantly, unlike other Beclin-1-derived peptides, MP1 exhibited no significant impact on autophagy in normal cells. MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis focusing on Beclin-1 derivatives and Wnt/β-catenin pathway., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44 + CD8 + memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs., 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.)

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1 (TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15 -deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15 -deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

Renal ischemia-reperfusion (I/R) can be precipitated by multiple clinical situations that lead to impaired renal function and associated mortality. The resulting tubular cell damage is the outcome of complex disorders including, an inflammatory process with an overproduction of cytokines. Here, diacerein (DIA), an inhibitor of proinflammatory cytokine interleukin-1 beta (IL-1β), was investigated against renal I/R in rats. DIA was orally administrated (50 mg/kg/day) for ten days before bilateral ischemia for 45 min with subsequent 2 hr. reperfusion. Interestingly, DIA alleviated the renal dysfunction and histopathological damage in the renal tissues. Pretreatment with DIA corrected the oxidative imbalance by prevented reduction in antioxidant levels of GSH and SOD, while it decreased the elevation of the oxidative marker, MDA. In addition, DIA downregulated IL-1β and TNF-α expression in the renal tissues. Consequent to inhibition of the oxidative stress and inflammatory cascades, DIA inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Therefore, downstream targets for p38 MAPK were also inhibited via DIA which prevented further increases of inflammatory cytokines and the apoptotic marker, caspase-3. Collectively, this study revealed the renoprotective role of DIA for renal I/R and highlighted the role of p38 MAPK encountered in its therapeutic application in renal disease., 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 Ltd. All rights reserved.)

Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLR family pyrin domain containing 3 (NLRP3) inflammasome, protein cell death-1, and Toll-like receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased p21 and p53 . Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased p16 and p19 . These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice. NEW & NOTEWORTHY Hypertension and obesity can lead to glomerular dysfunction in patients, causing podocyte injury and depletion. Here, young mice given deoxycorticosterone acetate or a high-fat diet to induce hypertension or obesity, respectively. mRNA sequencing of isolated podocytes showed transcriptional changes consistent with senescence, a senescent-associated secretory phenotype, and aging, which was confirmed by immunostaining. Ongoing studies are determining the mechanistic roles of the accelerated aging podocyte phenotype in experimental hypertension and obesity.

Epithelial cells (ECs) have been proposed to contribute to myofibroblasts or fibroblasts through epithelial-mesenchymal transition (EMT) during renal fibrosis. However, since EMT may occur dynamically, transiently, and reversibly during kidney fibrosis, conventional lineage tracing based on Cre-loxP recombination in renal ECs could hardly capture the transient EMT activity, yielding inconsistent results. Moreover, previous EMT research has primarily focused on renal proximal tubule ECs, with few reports of distal tubules and collecting ducts. Here, we generated dual recombinases-mediated genetic lineage tracing systems for continuous monitoring of transient mesenchymal gene expression in E-cadherin + and EpCAM + ECs of distal tubules and collecting ducts during renal fibrosis. Activation of key EMT-inducing transcription factor (EMT-TF) Zeb1 and mesenchymal markers αSMA, vimentin, and N-cadherin, were investigated following unilateral ureteral obstruction (UUO). Our data revealed that E-cadherin + and EpCAM + ECs did not transdifferentiate into myofibroblasts, nor transiently expressed these mesenchymal genes during renal fibrosis. In contrast, in vitro a large amount of cultured renal ECs upregulated mesenchymal genes in response to TGF-β, a major inducer of EMT., (© 2024 Wiley Periodicals LLC.)

Although great efforts have been made to elucidate the pathological mechanisms of renal diseases and potential prevention and treatment targets that would allow us to retard kidney disease progression, we still lack specific and effective management methods. Epigenetic mechanisms are able to alter gene expression without requiring DNA mutations. Accumulating evidence suggests the critical roles of epigenetic events and processes in a variety of renal diseases, involving functionally relevant alterations in DNA methylation, histone methylation, RNA methylation, and expression of various non-coding RNAs. In this review, we highlight recent advances in the impact of methylation events (especially RNA m 6 A methylation, DNA methylation, and histone methylation) on renal disease progression, and their impact on treatments of renal diseases. We believe that a better understanding of methylation modification changes in kidneys may contribute to the development of novel strategies for the prevention and management of renal diseases., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

One in 700 children is born with the down syndrome (DS). In DS, there is an extra copy of X chromosome 21 (trisomy). Interestingly, the chromosome 21 also contains an extra copy of the cystathionine beta synthase (CBS) gene. The CBS activity is known to contribute in mitochondrial sulfur metabolism via trans-sulfuration pathway. We hypothesize that due to an extra copy of the CBS gene there is hyper trans-sulfuration in DS. We believe that understanding the mechanism of hyper trans-sulfuration during DS will be important in improving the quality of DS patients and towards developing new treatment strategies. We know that folic acid "1-carbon" metabolism (FOCM) cycle transfers the "1-carbon" methyl group to DNA (H3K4) via conversion of s-adenosyl methionine (SAM) to s-adenosyl homocysteine (SAH) by DNMTs (the gene writers). The demethylation reaction is carried out by ten-eleven translocation methylcytosine dioxygenases (TETs; the gene erasers) through epigenetics thus turning the genes off/on and opening the chromatin by altering the acetylation/HDAC ratio. The S-adenosyl homocysteine hydrolase (SAHH) hydrolyzes SAH to homocysteine (Hcy) and adenosine. The Hcy is converted to cystathionine, cysteine and hydrogen sulfide (H 2 S) via CBS/cystathioneγ lyase (CSE)/3-mercaptopyruvate sulfurtransferase (3MST) pathways. Adenosine by deaminase is converted to inosine and then to uric acid. All these molecules remain high in DS patients. H 2 S is a potent inhibitor of mitochondrial complexes I-IV, and regulated by UCP1. Therefore, decreased UCP1 levels and ATP production can ensue in DS subjects. Interestingly, children born with DS show elevated levels of CBS/CSE/3MST/Superoxide dismutase (SOD)/cystathionine/cysteine/H 2 S. We opine that increased levels of epigenetic gene writers (DNMTs) and decreased in gene erasers (TETs) activity cause folic acid exhaustion, leading to an increase in trans-sulphuration by CBS/CSE/3MST/SOD pathways. Thus, it is important to determine whether SIRT3 (inhibitor of HDAC3) can decrease the trans-sulfuration activity in DS patients. Since there is an increase in H3K4 and HDAC3 via epigenetics in DS, we propose that sirtuin-3 (Sirt3) may decrease H3K4 and HDAC3 and hence may be able to decrease the trans-sulfuration in DS. It would be worth to determine whether the lactobacillus, a folic acid producing probiotic, mitigates hyper-trans-sulphuration pathway in DS subjects. Further, as we know that in DS patients the folic acid is exhausted due to increase in CBS, Hcy and re-methylation. In this context, we suggest that folic acid producing probiotics such as lactobacillus might be able to improve re-methylation process and hence may help decrease the trans-sulfuration pathway in the DS patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chronic kidney disease (CKD) has a high incidence and poor prognosis; however, no effective treatment is currently available. Our previous study found that the improvement effect of the herb pair of Rhubarb-Astragalus on CKD is likely related to the inhibition of the TGF-β1/p38-MAPK pathway. In the present study, a p38-MAPK inhibitor was used to further investigate the inhibitory effect of Rhubarb-Astragalus on the TGF-β1/p38-MAPK pathway and its relationship with autophagy., Methods: A rat model of unilateral ureteral obstruction (UUO) was established, and a subgroup of rats was administered Rhubarb-Astragalus. Renal function and renal interstitial fibrosis (RIF) were assessed 21 d after UUO induction. In vitro, HK-2 cells were treated with TGF-β1 and a subset of cells were treated with Rhubarb-Astragalus or p38-MAPK inhibitor. Western blotting, immunohistochemistry, and qRT-PCR analyses were used to detect the relevant protein and mRNA levels. Transmission electron microscopy was used to observe autophagosomes., Results: Rhubarb-Astragalus treatment markedly decreased the elevated levels of blood urea nitrogen, serum creatinine, and urinary N-acetyl-β-D-glucosaminidase; attenuated renal damage and RIF induced by UUO; and reduced the number of autophagosomes and lysosomes in UUO-induced renal tissues. Additionally, Rhubarb-Astragalus reduced the protein and mRNA levels of α-SMA, collagen I, LC3, Atg3, TGF-β1, p38-MAPK, smad2/3, and TAK1 in renal tissues of UUO rats. Rhubarb-Astragalus also reduced protein and mRNA levels of these indicators in vitro. Importantly, the effect of the p38-MAPK inhibitor was similar to that of Rhubarb-Astragalus., Conclusions: Rhubarb-Astragalus improves CKD possibly by downregulating autophagy via the p38-MAPK/TGF-β1 and p38-MAPK/smad2/3 pathways., Competing Interests: Conflict of interest All authors declare that there is no conflict of interest in this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate the mechanism by which Sini decoction (, SND) improves renal fibrosis (Rf) in rats based on transforming growth factor β1/Smad (TGF-β1/Smad) signaling pathway., Methods: Network pharmacology was applied to obtain potentially involved signaling pathways in SND's improving effects on Rf. The targets of SND drug components and the targets of Rf were obtained by searching databases, such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCSMP) and GeenCard. The intersection targets of two searches were obtained and underwent signaling pathway analysis using a Venn diagram. Then experimental pharmacology was utilized to prove and investigate the effects of SND on target proteins in the TGF-β1/Smad signaling pathway. The Rf rat model was established by unilateral ureteral occlusion (UUO). The expression levels of transforming growth factor, matrix metalloproteinase-9 (MMP-9), matrix metal protease-2 (MMP-2), connective tissue growth factor (CTGF), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined by Masson staining of rat renal tissue, and immunohistochemical methods. The expression levels of Smad3, Smad2, and Smad7 in renal tissue were determined by Western blotting (WB). The mechanism of the improving effects of SND on Rf was investigated based on TGF-β1/Smad signaling pathway., Results: A total of 12 drug components of Fuzi ( Radix Aconiti Lateralis Preparata ), 5 drug components of Ganjiang ( Rhizoma Zingiber ), and 9 drug components of Gancao ( Radix Glycy et Rhizoma ) were obtained from the database search, and 207 shared targets were found. A total of 1063 Rf targets were found in the database search. According to the Venn diagram, in total, 96 intersection targets were found in two database searches. The metabolic pathways involved included TGF-β signaling pathway, phosphatidylinositol-3-kinase/serine-threonine protein kinase signaling (PI3K/Akt) pathway, and hypoxia-inducible factor-1 (HIF-1) signaling pathway. Masson staining analysis showed that compared with the model group, the renal interstitial collagen deposition levels in the SSN and SND groups were significantly lower ( P < 0.05). Immunohistochemical analysis, compared with the control group, the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the model group were significantly decreased ( P < 0.05, P < 0.01), and the positive cell area expression levels of CTGF and TGF-β1 were significantly increased ( P < 0.01). Compared with the model group, the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the SSN and SND groups were significantly increased ( P < 0.05, P < 0.01), and the positive cell area expression levels of CTGF and TGF-β1 in the kidney tissue were significantly decreased ( P < 0.05, P < 0.01). WB results showed that the SSN group and the SND group could reduce the expression of Smad2 and Smad3 ( P < 0.05) and increase the expression of Smad7 ( P < 0.05).

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin., (© 2024. The Author(s).)