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Introduction: Obesity is a progressive chronic disease that is a renal risk factor. Renal hyperfiltration is an early stage in the development of chronic kidney disease (CKD). The objective of our study is to determine the prevalence of glomerular hyperfiltration in obese patients. Materials and Methods: This is a prospective and descriptive study conducted over a period of 4 months. All patients with BMI over 30 kg/m2 who do not have diabetes, hypertension or another apparent cause of CKD. Results: A total of 85 patients were included, the mean age was 41.96 years, with a female majority. The mean BMI was 38.24kg/m2 and the mean abdominal waist circumference was 114.57cm. Obesity was common in 55.88% and secondary in 44.11%. The prevalence of glomerular hyperfiltration was 85.18% by Cockcroft formula and 48.33% by MDRD formula. Discussion: Obesity is a risk factor for CKD, which promotes increased renal blood flow by vasodilation of the afferent glomerular arteriole, resulting in glomerular hyperfiltration that leads to a change in the glomerular barrier, increasing the risk of developing CKD. According to several studies, the Cockcroft formula is a better predictor of renal function in obese patients. A 51% increase in GFR in obese patients has been observed. In our study, the prevalence of glomerular hyperfiltration is 85.18% according to the Cockcroft formula. Conclusion: Obesity is a risk factor for CKD that needs to be carefully considered.&nbsp

The potential protective effects of mesenchymal stem cells (MSCs) on some kidney diseases have been reported. However, the effect of the fetal kidney–derived (FKD)MSCs on doxorubicin-induced nephropathy has not been studied yet. This study aimed to treat rats with doxorubicin-induced kidney injuries by transplantation of –FKD-MSCs. Twenty-four Sprague-Dawley rats were divided into three groups as control, doxorubicin nephropathy (Sham), and doxorubicin + MSC treated group. Serum biochemistry analysis was performed at the beginning and the end of the study. Functional changes in kidneys were evaluated by scintigraphy. In the doxorubicin nephropathy group, histopathological findings such as mesangial cell proliferation, tubular cast, and glomerular hypertrophy were observed, whereas in the MSC group these findings were significantly reduced. CD133 and CD24 positive immunoreactions were the most severe and frequently observed in the MSC group. While positive staining was detected in the tubular epithelium, there was no immunostaining observed in the glomerulus. The results showed that both functional and histological improvements were achieved in the MSC group compared to the Sham group. In conclusion, transplantation of fetal kidney - derived MSCs into patients with renal damage is thought to contribute to the healing of the renal tissue., Mezenkimal kök hücrelerin (MKH) bazı böbrek hastalıklarındaki potansiyel koruyucu etkileri bildirilmiştir. Bununla birlikte, fetal böbrek kaynaklı MKH'ların doksorubisin ile indüklenmiş nefropati üzerindeki etkisi henüz araştırılmamıştır. Bu çalışmanın amacı, doksorubisin kaynaklı böbrek hasarı olan ratlara fetal böbrek kaynaklı MKH'ların transplantasyonu yapılarak tedavi edilmesidir. Çalışmada yirmi dört adet Sprague – Dawley ırkı rat üç gruba ayrılmıştır. Bunlar: kontrol grubu, doksorubisin nefropatisi (Sham) grubu ve doksorubisin + MKH ile tedavi edilen gruptur. Çalışmanın başında ve sonunda ratlardan kan alınarak serum biyokimya çalışılmıştır. Böbreklerdeki fonksiyonel değişiklikler sintigrafi ile değerlendirilmiştir. Doksorubisin nefropatisi grubunda mezanjiyal hücre proliferasyonu, tübüler alçı ve glomerüler hipertrofi gibi histopatolojik bulgular gözlenirken, MKH grubunda bu bulgular anlamlı olarak azalmıştır. CD133 ve CD24 pozitif immünreaksiyonlar, en şiddetli ve en sık olarak MKH grubunda gözlenmiştir. Tübüler epitelde pozitif boyanma tespit edilirken glomerulusta immün boyanma gözlenmemiştir. Sonuçlar, Sham grubuna kıyasla MKH grubunda hem fonksiyonel hem de histolojik iyileşmelerin sağlandığını göstermiştir. Sonuç olarak, böbrek hasarı olan hastalara fetal böbrek kaynaklı MKH transplantasyonunun böbrek dokusunun iyileşmesine katkıda bulunduğu düşünülmektedir.

Contains fulltext : 234060.pdf (Publisher’s version ) (Open Access) Prematurity and perinatal stress, such as intrauterine growth restriction (IUGR) and chorioamnionitis, are pathological processes creating an impaired intrauterine environment. These intrauterine factors are associated with the development of proteinuria, hypertension, and chronic kidney disease (CKD) later in life. Initially, this was thought to be secondary to oligonephropathy, subsequent glomerular hypertrophy, and hyperfiltration, leading to glomerulosclerosis, a further decrease in nephron number, and finally CKD. Nowadays, there is increasing evidence that prematurity and perinatal stress affect not only nephron endowment but also the maturation of podocytes and vasculogenesis. IUGR is associated with podocyte damage and an aggravated course of nephrotic syndrome. Moreover, preterm birth and IUGR are known to cause upregulation of the postnatal renin-angiotensin system, resulting in hypertension. Chorioamnionitis causes damage to the glomeruli, thereby predisposing to the development of glomerulosclerosis. This review aims to summarize current knowledge on the influence of prematurity, IUGR, and chorioamnionitis on the development of different glomerular structures. After summarizing human and experimental data on low nephron number in general, a specific focus on the current understanding of podocyte and glomerular capillary formation in relation to prematurity and different causes of perinatal stress is presented.

The rising prevalence of obesity-related glomerulopathy (ORG) occurs in accordance with the rising prevalence of obesity worldwide. Clinically ORG is manifested by slowly progressing microalbuminuria that may develop to clinically evident proteinuria. Pathological characteristics of ORG include glomerular hypertrophy in the presence or absence of focal segmental glomerulosclerosis (FSGS). ORG can develop into clinically overt chronic renal insufficiency or even end-stage kidney disease. This article reviews the most important mechanisms for the development of ORG; that are abnormal renal hemodynamics, stimulation of renin-angiotensin-aldosterone system (RAAS), impairment of insulin sensetivity, ectopic lipid deposition, adipose tissue cytokine disorder and local renal micro-inflammation.

Background: Traditional medicine is increasingly favored by the community as an effort to maintain and treat health because it has low side effects and is easy to obtain. Low side effects in administering traditional medicines if the dosage is right, so it is necessary to do an acute toxicity test. One of the consumers of traditional medicine is diabetes mellitus (DM) sufferer. DM can cause delay wound healing. Toman fish is proven to accelerate wound healing. DM sufferers need special attention to their kidneys because in addition to the toxic effects caused by improper doses of traditional medicine, the kidneys can also experience diabetic nephropathy. Objectives: To analyze changes in glomerular hypertrophy and hydropic degeneration in the administration of 16 mL / KgBW Toman fish extract orally for 14 days in diabetic wistar rat kidneys. Methods: This study was a true experimental design with a post test only with control group design. The study was divided into a treatment group of toman fish extract at a dose of 16 mL / Kg BW orally for 14 days in diabetic rat kidney models and a control group in the form of feeding only. Results: The administration of toman fish extract in DM rat showed changes in the glomerular hypertrophy picture of 25-50% and decreased glomerular hypertrophy score which was significantly different from the control group. There was no feature of hydropic degeneration in either group. Conclusions: Giving toman fish extract to DM rat can reduce glomerular hypertrophy and does not cause hydropic degeneration

Objective: To observe the nephroprotective role of berberis vulgar is on renal parenchyma against microscopic and morphometric changes induced by Gentamicin in albino rats. Study Design: Lab based experimental study. Place and Duration of Study: It was conducted in Baqai Medical University in collaboration with department of Anatomy Liaquat National Hospital and Medical College, from Jan to Jul 2017. Methodology: A total of 40 male adult albino rats were used in the study. Four groups were made. Each group contained 10 rats. Group A was a control group, group B received only berberis vulgaris fruit extract orally per day for 21 days, group C received Gentamicin 100 mg/kg/day intraperitonially daily for 21 days. Group D received Gentamicin 100 mg/kg/day intraperitonially along with berberis vulgaris fruit extract 100 mg/kg/day orally. Both kidneys were removed. H&E and PAS stains were used for observing histological alterations and protective role of berberis vulgaris fruit extract. Results: Glomerulus and proximal convoluted tubules were observed histologically in all 4 groups. Microscopy of group B showed parameters nearly similar to control group. Microscopy of group C showed significant derangement in all parameters when compared with control group. Group C showed decrease glomerular, proximal convoluted tubular count was noted. Glomerular diameter increases and there was glomerular hypertrophy and tubular necrosis. Microscopy of group D showed significant improvement due to berberis vulgaris which restored normal renal architecture. Conclusion: Berberis vulgaris has a nephroprotective effect and it can be used as a new medicine against nephrotoxic drugs like Gentamicin.

Kidney aging is a normal physiological process associates with various molecular, morphologic and functional changes in the kidney tissues. This work was designed to study microscopically the structural changes in the kidney tissue of aged rats compared to young rats. Male Sprague–Dawley rats were used 10 young rats (4 months) and 10 aged rats (24 months). Rats were transcardially perfused with 4% paraformaldehyde. The kidneys were post fixed for 24 hours in 4 % PFA then proceeded for normal histopathology and light microscopic examination. Kidney tissue of aged rats showed serious morphological changes such as; segmental glomerulosclerosis, pericapsular fibrosis, tubulointerstitial fibrosis, perivascular fibrosis, inflammatory cell infiltration, tubular dilatation, intra-tubular cast formation and tubular atrophy. These changes were compared to the normal histological appearance of glomeruli, tubules, interstitium, blood vessels of young rat kidneys. In addition, the kidney tissue of the aged rats showed compensatory glomerular hypertrophy, tubular hyperplasia and endothelial proliferation. Renal aging involves several degenerative changes in kidney structure and these alterations interfere with the physiologic functions and end with chronic renal failure.

Background Previously, by using proteomic analysis and RNA sequencing in isolated glomeruli, we identified several novel differentially expressed proteins in human and mouse diabetic nephropathy (DN) versus controls, including dishevelled associated activator of morphogenesis 2 (DAAM2). DAAM2 binds the Wnt effector Dvl. We aimed to study possible contributions of DAAM2 to DN. Methods We assessed DAAM2 by immunostaining in non-cancer regions of human nephrectomy (Nx), DN and normal donor kidney tissues. We also examined DAAM2 in DN mice (db/db eNOS−/−) and Nx mice. DN mice treated with angiotensin-converting enzyme inhibitor (ACEI), dipeptidyl peptidase 4 inhibitor (DPP4I) or vehicle were compared. DAAM2 was knocked down in primary cultured podocytes by small interfering RNA to study its effects on cell function. Results In normal human glomeruli, DAAM2 was expressed only on podocytes. DAAM2 expression was increased in both Nx and DN versus normal donors. Podocyte DAAM2 expression was increased in DN and Nx mouse models. Glomerular DAAM2 expression correlated with glomerular size and was decreased significantly by ACEI while DPP4I only numerically reduced DAAM2. In primary cultured podocytes, knockdown of DAAM2 enhanced adhesion, slowed migration, activated Wnt–β-catenin signaling and downregulated mammalian target of rapamycin complex 1 (mTORC1) and Rho activity. Conclusions Podocyte DAAM2 is upregulated in both Nx and DN, which could be contributed to by glomerular hypertrophy. We hypothesize that DAAM2 regulates podocyte function through the mTORC1, Wnt/β-catenin and Rho signaling pathways.

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD). However, there are few tools to detect microstructural changes after AKI. Here, cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) was applied to examine the heterogeneity of kidney pathology in the transition from AKI to CKD. Adult male mice received folic acid followed by cationic ferritin and were euthanized at four days (AKI), four weeks (CKD-4) or 12 weeks (CKD-12). Kidneys were examined by histologic methods and CFE-MRI. In the CKD-4 and CKD-12 groups, glomerular number was reduced and atubular cortical lesions were observed. Apparent glomerular volume was larger in the AKI, CKD-4 and CKD-12 groups compared to controls. Glomerular hypertrophy occurred with ageing. Interglomerular distance and glomerular density were combined with other MRI metrics to distinguish the AKI and CKD groups from controls. Despite significant heterogeneity, the noninvasive (MRI-based) metrics were as accurate as invasive (histological) metrics at distinguishing AKI and CKD from controls. To assess the toxicity of cationic ferritin in a CKD model, CKD-4 mice received cationic ferritin and were examined one week later. The CKD-4 groups with and without cationic ferritin were similar, except the iron content of the kidney, liver, and spleen was greater in the CKD-4 plus cationic ferritin group. Thus, our study demonstrates the accuracy and safety of CFE-MRI to detect whole kidney pathology allowing for the development of novel biomarkers of kidney disease and providing a foundation for future in vivo longitudinal studies in mouse models of AKI and CKD to track nephron fate.

Obesity-related kidney disease is associated with generalized endothelial dysfunction. Liraglutide, a glucagon-like peptide-1 agonist, has cardiovascular-renal protective effects in patients with diabetes. In this study, the ability of liraglutide to reduce urinary albumin excretion by alleviating glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis uncoupling was assessed in high fat diet-induced obese mice. C57BL/6J mice were divided into control and obesity groups, treated with or without liraglutide (200 μg/kg/day). Blood biochemistry and urinary albumin excretion were measured. Glomerular VEGF and the AMPK-endothelial nitric oxide synthase (eNOS) pathway were assayed by western blotting. Glomerular NO, renal haeme oxygenase-1 activity, and malondialdehyde levels were also measured. Treatment of obese mice with liraglutide led to significant reductions in body weight gain (46 ± 1 g vs 55 ± 1 g, P

Diabetic nephropathy (DN) is the most serious end-stage renal disease which characterized by renal glomerular sclerosis including glomerular hypertrophy, glomerular basement membrane (GBM) thickening, mesangial expansion and renal fibrosis. TGF-β/Smads signal pathway plays a crucial role in the development of renal fibrosis. In this study, we found that GdCl3 which was an agonist of Calcium-sensing receptor (CaSR) could repress the activation of TGF-β/Smads signal pathway induced by TGF-β1 or high glucose and then alleviated the accumulation of extracellular matrix (ECM) in mesangial cells and the kidney of type1 diabetic rats. Further study indicated that GdCl3 could induce the binding of CaSR and TβR II and then both of these two receptors translocated from cell membrane to cytoplasm, in this case, TβR II on the cell membrane was decreased and then desensitized to the stimulation of its ligand TGF-β1, so that the activation of its downstream factors such as Smad2 and Smad3 were blocked, finally, ECM expression in mesangial cells were inhibited. We concluded that GdCl3 could alleviate the accumulation of ECM in mesangial cells via antagonizing TGF-β/Smads signal pathway in diabetes mellitus. ispartof: Journal of Pharmacological Sciences vol:142 issue:2 pages:41-49 ispartof: location:Japan status: published

Glomerular tuft immune reactive Ezrin surface area (EzA) and fraction of EzA to total glomerular tuft area significantly increased, indicating podocyte growth, rounding and altered cytoskeletal interactions at 1 week of STZ diabetes. Podocyte number per glomerulus (WT1+ nuclei) did not change indicating no detachment, but density decreased due to tuft hypertrophy. Treatment with PLZ or Insulin for one week, prevented increase in proteinuria and hyperglycemia but not the decrease in podocyte density. PLZ but not Insulin prevented increase in ezrin positive area in glomeruli and per podocyte. In podocytes in culture neither 25 mM glucose with or without PLZ (2.5 or 25 uM) altered Ezrin expression measured in western blots. In summary, the Ezrin positive glomerular surface area increase seen after 1 week of STZ diabetes, reflects altered podocyte morphology and cytoskeletal interactions, prevented by PLZ but not by insulin. Ezrin area increase preceded podocyte detachment and in podocytes in culture is not associated with increases in podocyte Ezrin protein expression. It is a likely precursor of shape changes in podocytes and of alterd interactions with basement membrane that contribute to detachment and thickening. Glomerular capillary tuft hypertrophy and reduced podocyte density persisted despite PLZ or insulin treatments, independently of levels of glycemia and of proteinuria.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD.

Background: Podocyte foot process effacement is a key histologic finding in proteinuric kidney disease. We previously showed that 3-week old CD2AP-deficient mice have significant proteinuria, glomerular hypertrophy and mesangial expansion. The goal of this study is to use morphometry to establish the temporal sequence of podocyte foot process effacement, glomerular volume expansion and albuminuria in Cd2ap−/− mice by measuring these parameters at the 2-week time point.Methods: Wild-type mice age 14 ± 1 days with the Cd2ap gene (WT, N = 5) and mice deficient for Cd2ap (Cd2ap KO, N = 5) were generated. Kidneys were harvested and fixed in 2.5% glutaraldehyde and processed for examination by light and electron microscopy. An average of 415.2 (range 268–716) grid points were counted for all the glomeruli, and quantification of glomerular volume from each kidney. Urine was collected the day prior to sacrifice for urine albumin-to-creatinine ratio (ACR) measurements.Results: There was no difference in albuminuria [median (range) mg/g] between WT [212.2 (177.6–388.4) mg/g] vs. Cd2ap KO mice [203.3 (164.7–910.2) mg/g], P = 0.89; or glomerular volume 68,307[10,931] vs. 66,844[13,022] μm3, p = 0.92. The volume densities of glomerular components of the podocyte, capillary lumen and mesangium were not different for the two groups, P = 0.14, 0.14 and 0.17 respectively. However, foot process width was increased in Cd2ap KO 1128[286] vs. WT [374 ± 42] nm, P = 0.02.Conclusion: Here we show that while 2-week old WT and Cd2ap KO mice have similar levels of albuminuria, glomerular and mesangial volume, Cd2ap KO mice have more extensive podocyte foot process effacement. The data suggests that podocyte injury is the initiating event leading to mesangial expansion and albuminuria in this model.

Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p p p p p p p p p p p p p Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation. Graphical abstract

Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy.

Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy “compensatory” glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.

Most of the obesity murine models inducing renal injury use calorie‐enriched foods, where fat represents 60% of the total caloric supply, however, this strategy doubles the standard proportion of fat ingestion in obese patients. Therefore, it is crucial to study the impact of a high‐fat intake on kidney physiology that resembles common obesity in humans to understand the trigger mechanisms of the long‐term consequences of overweight and obesity. In this study, we analyzed whether chronic feeding with a moderately high fat diet (MHFD) representing 45% of total calories, may induce kidney function and structural injury compared to C57BL/6 mice fed a control diet. After 14 weeks, MHFD induced significant mice obesity. At the functional level, obese mice showed signs of kidney injury characterized by increased albuminuria/creatinine ratio and higher excretion of urinary biomarkers of kidney damage. While, at the structural level, glomerular hypertrophy was observed. Although, we did not detect renal fibrosis, the obese mice exhibited a significant elevation of Tgfb1 mRNA levels. Kidney damage caused by the exposure to MHFD was associated with greater oxidative stress, renal inflammation, higher endoplasmic reticulum (ER)‐stress, and disruption of mitochondrial dynamics. In summary, our data demonstrate that obesity induced by a milder fat content diet is enough to establish renal injury, where oxidative stress, inflammation, ER‐stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long‐term consequences associated with obesity and metabolic syndrome., Here, we demonstrated that obesity induced by a MHFD is enough to establish kidney damage, where oxidative stress, renal inflammation, ER‐stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long‐term consequences associated with obesity.

Simple Summary The worldwide prevalence of diabetes mellitus (DM) in 2020 has been estimated at 463 million patients. About 90% of patients with diabetes have type 2 diabetes mellitus (T2D), caused primarily by insulin resistance and insufficiency. However, the specific etiology of T2D remains unknown. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a novel class of anti-diabetic drugs that act independently of insulin and reduce blood glucose concentrations by inhibiting the reabsorption of glucose at renal proximal tubules. SGLT2 inhibitors have highlighted the role of the kidneys in glycemic control in diabetes. The kidneys have multiple roles in systemic glucose metabolism, such as glucose reabsorption, gluconeogenesis, and insulin degradation. Therefore, putative renal hyperfunction might contribute to the development of T2D. The present study characterized rats from a strain of novel type 2 diabetes model with enlarged kidneys (DEK). Their kidneys have increased parenchyma (nephrons and tubules), and uninephrectomy immediately after the onset inhibited the development of T2D for a significant period in DEK rats. These results highlight the contribution of kidney to the development of T2D, and indicate that the kidneys are therapeutic targets to prevent T2D. Abstract The kidneys participate in the regulation of systemic glucose metabolism via gluconeogenesis, insulin degradation, and the tubular reabsorption of glucose. The present study characterized rats from a strain of a novel type 2 diabetes model with enlarged kidneys (DEK). Histological and biochemical analyses of DEK rats were performed to assess the relationships between their kidneys and hyperglycemia. The kidney weight of diabetic DEK (DEK-DM) gradually increased over time from the onset of diabetes, with the glomerular number being higher in DEK-DM than in normal DEK (DEK-cont). A positive correlation between blood glucose level and kidney weight was observed in DEK-DM. The similar glomerular size and single glomerular creatinine clearance in DEK-cont and DEK-DM indicated that glomerular hypertrophy and hyperfiltration were not involved in the renal enlargement. Uninephrectomy (1/2Nx) in DEK-DM resulted in a reduction in blood glucose level at 7–28 post-operation days, with this concentration remaining lower than in Sham group until 84 days post-operation. 1/2Nx also improved systemic conditions, including reduced body weight gain, polyuria, polydipsia, and hyperphagia. Plasma concentrations of Na, total cholesterol, albumin, and total protein were higher, and urinary excretion of glucose, urea nitrogen, and proteins were lower, in the 1/2Nx than in the Sham group. Remnant kidney weight was two-fold higher in the 1/2Nx than in the Sham group 84 days later. In addition, 1/2Nx resulted in renal tubular dilatation but not in the progression of fibrosis or glomerular lesions. Taken together, these findings indicate that enlarged kidneys were associated with the onset of diabetes and with the resistance to diabetic nephropathy in DEK-DM.

Introduction: Emerging treatments of diabetic kidney disease (DKD) include SGLT2 inhibitors and GLP-1 receptor agonists that are nephroprotective beyond their blood glucose lowering effects. To confirm the translatability of a mouse model for drug discovery in DKD, we tested the efficacy of an ACE inhibitor and a SGLT2 inhibitor in the reninAAV UNx db/db mouse model. Methods: Female db/db mice were injected with a renin-encoding adeno-associated virus construct (reninAAV) to induce hypertension and uninephrectomized (UNx). At 12 weeks of age, dosing with vehicle, lisinopril, empagliflozin, or the combination (combo) was initiated. Plasma and urine markers were measured after 12 weeks of dosing and terminal kidney samples were collected for 3D light sheet microscopy and 2D histology. Results: In reninAAV UNx db/db mice, treatment with empagliflozin and combo reduced fed BG and HbA1c compared to vehicle. Treatment with lisinopril and combo reduced urine ACR and KIM1-to-creatinine compared to vehicle, while treatment with empagliflozin alone worsened urine ACR. Glomerular hypertrophy as assessed by 3D imaging was reduced in combo treated reninAAV UNx db/db mice compared to vehicle, while treatment with empagliflozin alone worsened glomerular hypertrophy. The total number of glomeruli per kidney was unaffected by treatments. Compared to vehicle treatment, lisinopril and combo treatment reduced the fraction of score 3+4 glomeruli, and glomerulosclerosis index (GSI) was reduced by with lisinopril and combo treatment. Treatment with empagliflozin alone worsened GSI. Morphometric analyses showed that lisinopril and combo treatment reduced kidney CD11b and KIM1 load. Conclusion: Responses to the combination treatment with lisinopril and empagliflozin showed improvement of urine and histological markers of DKD. Together, these data confirm the translatability of the reninAAV UNx db/db mouse model of DKD. Disclosure M. V. Østergaard: None. M. Christensen: None. T. Secher: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Self; Gubra, Stock/Shareholder; Spouse/Partner; Novo Nordisk. J. L. Skytte: None. U. Roostalu: Employee; Self; Gubra. C. G. Salinas: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Spouse/Partner; Novo Nordisk. F. E. Sembach: None. L. N. Fink: Employee; Self; Gubra, Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra, Employee; Self; Gubra, Stock/Shareholder; Self; Gubra.