scholarly journals A hyaluronan synthesis inhibitor delays progression of diabetic kidney disease in a mouse experimental model

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004642020
Author(s):  
Guillermo Selman ◽  
Laisel Martinez ◽  
Andrea Lightle ◽  
Alejandra Aguilar ◽  
Daniel Woltmann ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Plasma Glucose ◽  
Diabetic Kidney Disease ◽  
Control Diet ◽  
Experimental Period ◽  
Glomerular Injury ◽  
Synthesis Inhibitor ◽  
Diabetic Kidney ◽  
Injury Index ◽  
And Control

Background: The role of hyaluronan (HA) in the development and progression of diabetic kidney disease (DKD), as well as the precise mechanisms and consequences of HA involvement in this pathology are still to be clarified. Methods: In this study, we assayed the effects of the HA synthesis inhibitor 4-methylumbelliferone (4-MU) on the development of DKD. Diabetic type 2 model mice (eNOS-/- C57BLKS/Jdb) were fed artificial diets containing 5% 4-MU or not for 9 weeks. Plasma glucose, glomerular filtration rate (GFR), albumin to creatinine ratio (ACR), and biomarkers of kidney function and systemic inflammation were measured at baseline and after treatment. Diabetic nephropathy was further characterized in treated and control mice by histopathology. Results: Treated animals consumed a daily dose of approximately 6.2 g of 4-MU per kg of body weight. At the end of the experimental period, the 4-MU supplemented diet resulted in a significant decrease in non-fasting plasma glucose (516 [interquartile range 378-1170] vs. 1149 [875.8-1287] mg/dL, P=0.050) and a trend toward lower HA kidney content (5.6 ± 1.5 vs. 8.8 ± 3.1 ng/mg of kidney weight, P=0.070) compared to the control diet, respectively. Diabetic animals treated with 4-MU showed significantly higher GFR and lower urine ACR and plasma cystatin C levels than diabetic controls. Independent histological assessment of DKD also demonstrated a significant decrease in mesangial expansion score and glomerular injury index in 4-MU-treated mice compared to controls. Plasma glucose showed a strong correlation with kidney HA levels (r=0.66, P=0.0098). Both total hyaluronan (r=0.76, P=0.0071) and low-molecular-weight hyaluronan content (r=0.64, P=0.036) in the kidneys correlated with urine ACR in mice. Conclusion: These results show that the hyaluronan synthesis inhibitor 4-MU effectively slowed the progression of DKD and constitutes a potential new therapeutic approach to treat DKD.

scholarly journals Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats

2021 ◽  
Author(s):  
Denisha R Spires ◽  
Oleg Palygin ◽  
Vladislav Levchenko ◽  
Elena Isaeva ◽  
Christine A. Klemens ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Risk ◽  
Plasma Cholesterol ◽  
Cardiovascular Disease Risk ◽  
Glomerular Injury ◽  
Diabetic Kidney ◽  
Age Related

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end-stage renal failure and increases cardiovascular disease risk. Hyperglycemia promotes renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity- and age-related risk factors. This study aimed to define sexual dimorphism and renal function in a non-obese type 2 diabetes model with the spontaneous development of advanced diabetic nephropathy (T2DN rats). T2DN rats at 12- and over 48-weeks old were used to define disease progression and kidney injury development. We found impaired glucose tolerance and glomerular hyperfiltration in T2DN rats to compare with non-diabetic Wistar control. The T2DN rat displays a significant sexual dimorphism in insulin resistance, plasma cholesterol, renal and glomerular injury, urinary nephrin shedding, and albumin handling. Our results indicate that both male and female T2DN rats developed non-obese type 2 DKD phenotype, where the females had significant protection from the development of severe forms of DKD. Our findings provide further evidence for the T2DN rat strain's effectiveness for studying the multiple facets of DKD.

scholarly journals Urinary Markers of Glomerular Injury in Diabetic Nephropathy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Abraham Cohen-Bucay ◽  
Gautham Viswanathan
Keyword(s):  
Renal Failure ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Current Literature ◽  
Cardiovascular Events ◽  
Diabetic Kidney Disease ◽  
Glomerular Injury ◽  
Diabetic Kidney ◽  
Urinary Markers

Diabetic nephropathy, the leading cause of renal failure worldwide, affects approximately one-third of all people with diabetes. Microalbuminuria is considered the first sign and the best predictor of progression to renal failure and cardiovascular events. However, albuminuria has several limitations. Therefore, earlier, more sensitive and specific biomarkers with greater predictability are needed. The aim of this paper is to discuss the current literature on biomarkers of glomerular injury that have been implicated in diabetic kidney disease.

scholarly journals Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease

2019 ◽  
Author(s):  
Yu Ho Lee ◽  
Ki Pyo Kim ◽  
Sun-Hwa Park ◽  
Dong-Jin Kim ◽  
Yang-Gyun Kim ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Renal Outcome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glomerular Injury ◽  
Tubular Atrophy ◽  
Diabetic Kidney ◽  
Cytokines And Chemokines ◽  
Pathologic Features

Abstract Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P = 0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

scholarly journals SUN-311 NF-KAPPA B ACTIVATION PROMOTES GLOMERULAR INJURY AND INFLAMMATION IN LONG-TERM EXPERIMENTAL DIABETIC KIDNEY DISEASE

2019 ◽  
Vol 4 (7) ◽  
pp. S289
Author(s):  
O. FORESTO-NETO ◽  
A.H. Albino ◽  
S.C.A. Arias ◽  
V.D. Faustino ◽  
F.F.F. Zambom ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Glomerular Injury ◽  
Nf Kappa B ◽  
Diabetic Kidney

scholarly journals Correlations between SIRT1 gene polymorphisms and diabetic kidney disease

2018 ◽  
Vol 5 (6) ◽  
pp. 171871 ◽  
Author(s):  
Xin-Ge Yue ◽  
Zai-Gang Yang ◽  
Yue Zhang ◽  
Gui-Jun Qin ◽  
Fei Liu
Keyword(s):  
Kidney Disease ◽  
Gene Polymorphisms ◽  
Diabetic Kidney Disease ◽  
Susceptibility Gene ◽  
Albumin Excretion Rate ◽  
Control Group ◽  
Diabetic Kidney ◽  
Significant Difference ◽  
Sirt1 Gene ◽  
And Control

To investigate the correlations between SIRT1 gene polymorphisms and diabetic kidney disease (DKD). There were 150 patients with DKD in the observation group (urinary albumin excretion rate (UAER) ≥ 300 mg 24 h −1 ), and 160 patients with a more than 10 year history of type 2 diabetes but without retinopathy and DKD (UAER < 30 mg 24 h −1 ) in the control group. Genotypes of three tagged single-nucleotide polymorphism loci (rs3818292, rs4746720 and rs10823108) in the SIRT1 gene in the two groups were detected. Risks of DKD for patients with the GG and GG + AG genotype in the rs10823108 locus of the SIRT1 gene were 2.96 and 2.92 times higher than that for AA genotype carriers, respectively. The risk of DKD for patients with the GG genotype in the rs3818292 locus was 0.23 times and 0.21 times higher than that for AA and for AA + AG genotype carriers, respectively, and the risk of DKD for patients with allele G was 0.66 times higher than that for allele A carriers. There was no significant difference in genotype frequency of rs4746720 locus gene polymorphisms between the observation and control groups. The SIRT1 gene is a genetic susceptibility gene of DKD. Mutation genotype GG and GG + AG in the rs10823108 locus can increase the risk of DKD. Mutation genotype GG and allele G in the rs3818292 locus can decrease the risk of DKD.

scholarly journals Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease

2020 ◽  
Vol 318 (5) ◽  
pp. F1067-F1073
Author(s):  
Shohei Mitsui ◽  
Yuji Oe ◽  
Akiyo Sekimoto ◽  
Emiko Sato ◽  
Yamato Hashizume ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Therapeutic Option ◽  
Collagen Type Iv ◽  
Type I ◽  
Glomerular Injury ◽  
Plasminogen Activator Inhibitor 1 ◽  
Diabetic Kidney ◽  
Dual Blockade ◽  
Akita Mice

Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg·kg−1·day−1), PAR2 antagonist (FSLLRY, 3 mg·kg−1·day−1), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 + FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NF-κB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-κB inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.

scholarly journals Extracellular vesicle-derived AEBP1 mRNA as a novel candidate biomarker for diabetic kidney disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yiying Tao ◽  
Xing Wei ◽  
Yue Yue ◽  
Jiaxin Wang ◽  
Jianzhong Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Tissue ◽  
Extracellular Vesicle ◽  
Clinical Parameter ◽  
Diagnostic Efficacy ◽  
Diabetic Kidney ◽  
Efficacy Assessment ◽  
Novel Biomarkers ◽  
And Control

Abstract Background A novel and improved methodology is still required for the diagnosis of diabetic kidney disease (DKD). The aim of the present study was to identify novel biomarkers using extracellular vesicle (EV)-derived mRNA based on kidney tissue microarray data. Methods Candidate genes were identified by intersecting the differentially expressed genes (DEGs) and eGFR-correlated genes using the GEO datasets GSE30528 and GSE96804, followed by clinical parameter correlation and diagnostic efficacy assessment. Results Fifteen intersecting genes, including 8 positively correlated genes, B3GALT2, CDH10, MIR3916, NELL1, OCLM, PRKAR2B, TREM1 and USP46, and 7 negatively correlated genes, AEBP1, CDH6, HSD17B2, LUM, MS4A4A, PTN and RASSF9, were confirmed. The expression level assessment results revealed significantly increased levels of AEBP1 in DKD-derived EVs compared to those in T2DM and control EVs. Correlation analysis revealed that AEBP1 levels were positively correlated with Cr, 24-h urine protein and serum CYC and negatively correlated with eGFR and LDL, and good diagnostic efficacy for DKD was also found using AEBP1 levels to differentiate DKD patients from T2DM patients or controls. Conclusions Our results confirmed that the AEBP1 level from plasma EVs could differentiate DKD patients from T2DM patients and control subjects and was a good indication of the function of multiple critical clinical parameters. The AEBP1 level of EVs may serve as a novel and efficacious biomarker for DKD diagnosis.

scholarly journals Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

2021 ◽  
Author(s):  
Hua Qu ◽  
Xiaoli Gong ◽  
Xiufei Liu ◽  
Rui Zhang ◽  
Yuren Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Glycerol 3 Phosphate Dehydrogenase

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, <a>contributing</a> to the global burden of kidney failure, cardiovascular morbidity and death. The key cell <a>type</a> that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we <a>characterized</a> the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated <a>diabetes-</a> or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury <a>significantly improved</a> their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

scholarly journals Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

2021 ◽  
Author(s):  
Hua Qu ◽  
Xiaoli Gong ◽  
Xiufei Liu ◽  
Rui Zhang ◽  
Yuren Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Glycerol 3 Phosphate Dehydrogenase

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, <a>contributing</a> to the global burden of kidney failure, cardiovascular morbidity and death. The key cell <a>type</a> that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we <a>characterized</a> the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated <a>diabetes-</a> or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury <a>significantly improved</a> their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

P0129DIET INDUCED ACCELERATION OF RENAL INJURY IN THE BTBROB/OB MOUSE MODEL OF DIABETIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Lena William-Olsson ◽  
Pernilla Tonelius ◽  
Tajana Tesan Tomic ◽  
Magnus Söderberg ◽  
Anna Björnson Granqvist
Keyword(s):  
Gene Expression ◽  
Kidney Disease ◽  
Mouse Model ◽  
Disease Progression ◽  
Diet Composition ◽  
Diabetic Kidney Disease ◽  
Control Diet ◽  
Physical Parameters ◽  
Chow Diet ◽  
Diabetic Kidney

Abstract Background and Aims There is a need of disease relevant models for efficient evaluation of new drug targets in the renal field. The obese diabetic BTBRob/ob mouse model have features resembling important aspects of human diabetic kidney disease and is extensively used in pharmacological studies. Since diet composition plays a role in diabetic- and renal disease it is important to have detailed control of nutritional intake in our pre-clinical models, especially since many studies use in-diet drug administration. In this study we compared disease progression in obese diabetic mice on non-defined chow diet (R3) with the defined control diet D12450B (Research Diets). Method BTBRob/ob mice were fed either regular laboratory rodent chow (R3) or the defined control diet D12450B containing 35% sucrose from 6 weeks of age. The animals were studied for 14 to 20 weeks of age and both physical parameters, urine and blood parameters, histology and gene expression was examined. (R3 group n=14, D12450B group n=8). Results Mice on the defined D12450B diet displayed increased calorie- and water intake, but gained less weight compared to R3 group. Blood glucose and HbA1c was higher at all timepoints, and urinary albumin-to-creatinine ratio was highly elevated compared to mice on R3 diet. Mice fed D12450B also displayed lower levels of plasma insulin and increased plasma b-hydroxybutyrate levels. Histopathological evaluation revealed that the defined D12450B diet increased induction both of mesangial injury score and gene expression of tubular injury markers NGAL and Kim-1. Conclusion : In summary, the choice of diet composition will have a huge impact on the disease progression in diabetic leptin-deficient overeating mouse models. These finding underline the importance of describing the diet composition in detail and take precaution on diet selection for preclinical studies.

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