P0984SGLT2 INHIBITION PREVENTS RENAL FIBROSIS IN CYCLOSPORINE NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Tyrosine Hydroxylase ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Control Group ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Type 2 Diabetic Patients ◽  
Inflammatory Infiltrates

Abstract Background and Aims Sodium glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, showed nephroprotection in type 2 diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is unclear whether the nephroprotective effects are present also in non-diabetic nephropathy. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, in cyclosporine nephropathy in the absence of diabetes. Method Ten days before the beginning and then during the entire experimental periods, low-salt diet (Teklad 7034) was administered to Sprague Dawley rats. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection; n=6) and CsA plus empagliflozin (Empa, 10 mg/kg /day, per os; n=6) were administered for 4 weeks. Control group was treated with placebo (n=6). Blood pressure was measured by plethysmographic method at the beginning and at the end of the experimental period. At the end of the protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and tyrosine hydroxylase expression, used as marker of symphatetic nerve activity. Results The rats treated with CsA showed a significant increase (p <0.01) in blood pressure, which was slightly reduced by administration of empagliflozin. CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p <0.05), renal inflammatory infiltrates (p <0.05) and tyrosine hydroxylase expression (p <0.01) as compared to the control rats. Treatment with empagliflozin reduced glomerular and tubulo-interstitial fibrosis (p <0.05), inflammatory cell infiltration (p <0.01) and tyrosine hydroxylase expression (p <0.01), as compared to CsA-treated rats. Conclusion Empagliflozin administration showed protective effects on cyclosporine nephropathy, decreasing renal fibrosis, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that the nephroprotective role of empagliflozin could not be restricted only to diabetic nephropathy.

Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension

2020 ◽  
Vol 51 (2) ◽  
pp. 119-129 ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Diabetic Patients ◽  
Type I ◽  
Ang Ii ◽  
Collagen Expression ◽  
Sodium Glucose Cotransporter ◽  
Inflammatory Infiltrates

Background: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. Methods: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. Results: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). Conclusions: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in Ang II-dependent hypertension. In Ang II-dependent hypertension, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is independent on the modulation of blood pressure increase.

scholarly journals Sodium-glucose cotransporter 2 inhibition prevents renal fibrosis in cyclosporine nephropathy

2021 ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Tyrosine Hydroxylase ◽  
Renal Fibrosis ◽  
Type Iv Collagen ◽  
Interstitial Fibrosis ◽  
Experimental Period ◽  
Type I ◽  
Collagen Expression ◽  
Type Iv ◽  
Inflammatory Infiltrates

Abstract Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, are nephroprotective in case of diabetes, but whether a similar beneficial effect may be detectable also in case of chronic non-diabetic kidney diseases remains still unknown. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, on the progression of cyclosporine nephropathy, in the absence of diabetes. Methods Sprague Dawley rats (n = 27) have been fed with low-salt diet starting 10 days before the beginning and finished at the end of the experimental period. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection, n = 8) and CsA plus empagliflozin (Empa, 10 mg/kg/day, per os, n = 7) were administered for 4 weeks. The control groups were treated with placebo (Control, n = 7) or empagliflozin (Control + Empa, n = 5). Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental period. At the end of the experimental protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages), type I and type IV collagen expression, and tyrosine hydroxylase expression, used as marker of sympathetic nerve activity. Results CsA-treated rats showed a significant increase (p < 0.01) in blood pressure, which was reduced by administration of empagliflozin (p < 0.05). CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p < 0.05), renal inflammatory infiltrates (p < 0.05), type I and type IV collagen expression (p < 0.01), and tyrosine hydroxylase expression (p < 0.01) as compared to the control rats and control + Empa-treated rats. Treatment with empagliflozin in CsA-treated rats reduced glomerular (p < 0.01) and tubulo-interstitial fibrosis (p < 0.05), type I and type IV collagen expression (p < 0.01), inflammatory cell infiltration (p < 0.01) and tyrosine hydroxylase expression (p < 0.05), as compared to rats treated with CsA. Conclusion Empagliflozin administration caused a reduction in blood pressure in CsA-treated rats and showed a protective effect on CsA nephropathy by decreasing renal fibrosis, type I and type IV collagen expression, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that empagliflozin promotes nephroprotection also in non-diabetic kidney disease.

scholarly journals The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy

2008 ◽  
Vol 27 (3) ◽  
pp. 376-382 ◽  
Author(s):  
Tatjana Cvetković ◽  
Predrag Vlahović ◽  
Vidosava đorđević ◽  
Lilika Zvezdanović ◽  
Dušica Pavlović ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Urine Concentration ◽  
Control Group ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Urinary Markers ◽  
Stress Markers

The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy Oxidative stress is considered to be a unifying link between diabetes mellitus (DM) and its complications, including nephropathy (DN). The aim of this study was to determine the parameters of oxidative injury of lipids and proteins as well as the activity of ectoenzymes in the urine of DN patients. The study included 40 individuals: 10 patients with type 2 diabetes mellitus and microalbuminuria (DMT2-MIA), 10 type 2 diabetic patients with macroalbuminuria (DMT2-MAA), 10 patients with type 1 diabetes and microalbuminuria (DMT1-MIA) and 10 age- and sex-matched healthy subjects (control). In the urine we determined TBA reactive substances (TBARS), reactive carbonyl groups (RCG), and the activity of ectoenzymes N-acetyl-β-d-glucosaminidase (NAG), plasma cell differentiation antigen (PC-1), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV). A higher concentration of TBARS in the urine was found in DMT2-MIA and DMT1-MIA, compared to the control group (p<0.001 and P<0.05). The urine concentration of RCD shows similar results with a significant elevation in the groups with DMT2-MAA and DMT1-MIA, compared to the DMT2-MIA (p<0.001) and control group (p<0.001). Activities of NAG, APN and DPPIV were significantly higher in the urine of DMT2-MAA, compared to the control (p<0.01). The activity of PC-1 was slightly increased in that group, but not significantly. In conclusion, the level of oxidative stress markers and activities of brush border ectoenzymes in the urine may be a useful non-invasive and easily repeatable test in DN.

scholarly journals Evaluation of urinary L-FABP as an early marker for diabetic nephropathy in type 2 diabetic patients

2019 ◽  
Vol 0 (0) ◽  
Author(s):  
Duong Thi Thuy Ngan ◽  
Nguyen Gia Binh ◽  
Le Thi Huong Lan ◽  
Cuc Thi Thu Nguyen ◽  
Phung Thanh Huong
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Early Detection ◽  
Urinary Albumin ◽  
Control Group ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Fatty Acid Binding ◽  
Type 2 Diabetic

Summary Background Albuminuria is the standard biomarker for the diagnosis of diabetic nephropathy (DN). However, some patients with persistent microalbuminuria still progress to chronic kidney disease, raising the question of finding a better biomarker. This study aimed to evaluate the correlation of urinary liver-type fatty acid-binding protein (L-FABP) levels with renal function and to compare the role of urinary albumin-to-creatinine ratio (ACR) with urinary L-FABP in early detection of DN in type 2 diabetic patients. Methods The cross-sectional study was done on 106 type 2 diabetic patients and 30 non-diabetic people. L-FABP was measured with the Latex enhanced immunoturbidimetric technique. Results There was a strong and negative correlation between the urine L-FABP levels and eGFR (r = -0.606, p<0.001). The urinary L-FABP levels were significantly higher (p<0.001) in the normoalbuminuria diabetic group than the non-diabetic control group. The ROC-curve analyses in the diabetic patients and the normoalbuminuria diabetic patients showed that the AUCL-FABP was remarkably higher (p<0.001) than the AUCACR. An optimal cutoff value of 5 mg L-FABP/g Cr (with the sensitivity of 98.1% and specificity of 90%) and of 4.3 mg L-FABP/g Cr (with the sensitivity of 100% and specificity of 86.67%) was set to detect DN in the diabetic patients and the normoalbuminuria diabetic patients, respectively. Conclusions The change in urinary L-FABP levels happened earlier than in urinary albumin during renal function impairment. Urinary L-FABP can be used as a better indicator than ACR for early detection of DN in type 2 diabetes.

scholarly journals Short-term renoprotective effect of SGLT-2 inhibitor for renal function and albuminuria in type 2 diabetes: a retrospective study

2020 ◽  
Author(s):  
Mitsunobu Kubota ◽  
Eri Shiroyama ◽  
Kanako Tanaka ◽  
Yoko Yoshii
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Renal Protection ◽  
Short Term ◽  
Type 2 Diabetic Patients ◽  
Before And After ◽  
Type 2 Diabetic

Abstract Background Progression of diabetic nephropathy in type 2 diabetic patients is a factor that determines the prognosis of life. Empagliflozin and canagliflozin, two oral diabetic SGLT-2 inhibitors, have shown improved renal outcomes in type 2 diabetic patients with chronic kidney disease in a large clinical study. These results suggest that SGLT-2 inhibitors could be used not only for hypoglycemic effects, but also for renal protective effects in patients with type 2 diabetes. It is not fully understood in which contexts the use of SGLT-2 inhibitors is likely to exert its renal protective effects. The purpose of this study was to clarify the profiles of patients in whom SGLT-2 inhibitors are more likely to exert a renal protective effect in clinical practice. We examined renal function and urinary albumin changes in short-term use of SGLT-2 inhibitors by patient background. Methods We retrospectively analyzed the medical record information of sixty-three type 2 diabetic patients (33 males, 30 females, average age 53.0 ± 13.0 years) who were given usual doses of a SGLT-2 inhibitor. We investigated changes in body weight, blood pressure, glucose metabolism index, lipid metabolism index, estimated glomerular filtration rate (eGFR) and albuminuria (urinary albumin-to-creatinine ratio, UACR) three months before and after administration of a SGLT-2 inhibitor. Results Three months after administration of an SGLT-2 inhibitor, there were improvements in glucose tolerance, weight loss, blood pressure, and lipid indices. In all cases, there was no significant change in eGFR, but UACR decreased significantly. UACR decreased regardless of Angiotensin II Receptor Blocker medication and significantly decreased in nephropathy patients with microalbuminuria or overt albuminuria. UACR decreased only in the group in which blood pressure, body weight, and hemoglobin A1c decreased before and after administration of the SGLT-2 inhibitor. Conclusions Our study shows that the renoprotective effects of SGLT-2 inhibitors are more likely to be exerted in diabetic nephropathy patients who have advanced to at least microalbuminuria stage, and in addition to direct renal protection, the comprehensive effects of SGLT-2 inhibitors, which lower body weight, blood pressure, and blood glucose, are also important for their renal protection effects.

scholarly journals Renal Effects of Sulodexide in Type 2 Diabetic Patients without Nephrotic Range Proteinuria

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Kachonsak Yongwatana ◽  
Ouppatham Supasyndh ◽  
Bancha Satirapoj
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Renal Function ◽  
Diabetic Nephropathy ◽  
Control Group ◽  
Diabetic Patients ◽  
Long Term Effects ◽  
Renal Disease Progression ◽  
Significant Difference

Background. Glycosaminoglycan plays an important role in the maintenance of glomerular charge selectivity of diabetic nephropathy. Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has shown a nephroprotective effect in an experimental model of diabetic nephropathy. Although sulodexide reduced albuminuria in patients with type 1 and type 2 diabetes, long-term effects in patients with type 2 diabetes with significant proteinuria have not been established. Objectives. The study was aimed at investigating the effects of sulodexide on proteinuria and renal function in patients with type 2 diabetes and nephropathy. Methods. Fifty-two patients with proteinuria between 500 and 3000 mg/day received sulodexide 200 mg/day for 12 months, while 56 matched patients with type 2 diabetes constituted the control group. All patients received standard metabolic and blood pressure controls. Primary outcome was evaluated as percentage of reduced proteinuria compared with the control group. Renal function was assessed using estimated glomerular filtration rate (GFR). Results. Proteinuria significantly increased in the control group [0.9 (IQR 0.3 to 1.78) to 1.16 (IQR 0.44 to 2.23) g/gCr, P=0.001], whereas it remained stable in the sulodexide group [0.66 (IQR 0.23 to 0.67) to 0.67 (IQR 0.17 to 1.51) g/gCr, P=0.108]. At 12 months, proteinuria was higher by 19.4% (IQR 10.3 to 37.6) in the control group while proteinuria was lower by -17.7% (IQR -53.1 to 3.2) in the sulodexide group with a significant difference between groups (P=0.001). Renal function was noted as a change of estimated GFR, and serum creatinine decreased significantly during the study in both groups but did not significantly differ between groups. No significant changes in the blood pressure, fasting plasma glucose, and hemoglobin A1C were reported. Conclusion. In addition to standard treatment, sulodexide is efficient in maintaining proteinuria in patients with type 2 diabetes with nonnephrotic range proteinuria, but it did not provide an additional benefit concerning renal disease progression.

scholarly journals Short-term renoprotective effect of SGLT-2 inhibitor for renal function and albuminuria in type 2 diabetes

2020 ◽  
Author(s):  
Mitsunobu Kubota ◽  
Eri SHiroyama ◽  
Kanako Tanaka ◽  
Yoko Yoshii
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Renal Protection ◽  
Short Term ◽  
Type 2 Diabetic Patients ◽  
Before And After ◽  
Type 2 Diabetic

Abstract Background Progression of diabetic nephropathy in type 2 diabetic patients is a factor that determines the prognosis of life. Empagliflozin and canagliflozin, two oral diabetic SGLT-2 inhibitors, have shown improved renal outcomes in type 2 diabetic patients with chronic kidney disease in a large clinical study. These results suggest that SGLT-2 inhibitors could be used not only for hypoglycemic effects, but also for renal protective effects in patients with type 2 diabetes. It is not fully understood in which contexts the use of SGLT-2 inhibitors is likely to exert its renal protective effects. The purpose of this study was to clarify the profiles of patients in whom SGLT-2 inhibitors are more likely to exert a renal protective effect in clinical practice. We examined renal function and urinary albumin changes in short-term use of SGLT-2 inhibitors by patient background. Methods We retrospectively analyzed the chart information of sixty-three type 2 diabetic patients (33 males, 30 females, average age 53.0 ± 13.0 years) who were given usual doses of a SGLT-2 inhibitor. We investigated changes in body weight, blood pressure, glucose metabolism index, lipid metabolism index, estimated glomerular filtration rate (eGFR) and albuminuria (urinary albumin-to-creatinine ratio, UACR) three months before and after administration of a SGLT-2 inhibitor. Results Three months after administration of an SGLT-2 inhibitor, there were improvements in glucose tolerance, weight loss, blood pressure, and lipid indices. In all cases, there was no significant change in eGFR, but UACR decreased significantly. UACR decreased regardless of Angiotensin II Receptor Blocker medication and significantly decreased in the nephropathy stage 2 and 3 groups. UACR decreased only in the group in which blood pressure, body weight, and HbA1c decreased before and after administration of the SGLT-2 inhibitor. Conclusions Our study shows that SGLT-2 inhibitors are independent of renin-angiotensin system (RAS) inhibitors, and in addition to direct renal protection, the comprehensive effects of SGLT-2 inhibitors, which lower body weight, blood pressure, and blood glucose, are also important for their renal protection effects.

scholarly journals Influence of HbA1c on short-term blood pressure variability in type 2 diabetic patients with diabetic nephropathy

2013 ◽  
Vol 14 (11) ◽  
pp. 1033-1040 ◽  
Author(s):  
Fang Liu ◽  
Min Wu ◽  
Yan-huan Feng ◽  
Hui Zhong ◽  
Tian-lei Cui ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Blood Pressure Variability ◽  
Diabetic Patients ◽  
Short Term ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

scholarly journals Prevalence of Nephropathy with Evaluation of HbA1c Level and other Associated Risk Factors in Type 2 Diabetic Patients in a Tertiary Level Hospital

KYAMC Journal ◽  
2017 ◽  
Vol 8 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Sayama Hoque ◽  
MA Muttalib ◽  
Md Imtiajul Islam ◽  
Parvin Akter Khanam ◽  
Nasrin Akter ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Logistic Regression ◽  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Univariate Analysis ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Background: Diabetes is the leading cause of chronic kidney disease which ultimately results end-stage renal disease (ESRD).Objectives: The purpose of the study was to explore the factors influencing or related to the development of the diabetic nephropathy with specific concern to the HbA1c (glycosylated hemoglobin) levels.Methods: Four hundred type 2 diabetic patients (male 166 and female 234) were studied and were evaluated for the presence of nephropathy through the review of their registered diabetic guide book. Glycaemic status was assessed by HbA1c (HbA1c was categorized into 3 groups) and plasma glucose levels. We used Student's ttest,?2-test and logistic regression analysis to determine and quantify the association of diabetic nephropathy with various risk factors specially HbA1c.Results: The prevalence of nephropathy was 24.0%; male 27.1%, female 21.8%. Increasing HbA1c categories above 7.0% were significantly associated with increased prevalence of nephropathy (15.8 vs 22.8 vs 30.7%; ?2 = 8.590, p = .013). Logistic regression models of univariate analysis showed that the risk of nephropathy was strongly increased at the HbA1c categories 8% (OR = 2.35; 95% CI: 1.30-4.25). Advanced age (OR = 3.8; 95% CI: 2.21-6.53), longer duration of diabetes (OR = 4.05; 95% CI: 2.31-7.10), lacking of physical exercise (OR = 1.93; 95% CI: 1.20-3.10), presence of hypertension (OR = 4.62; 95% CI: 2.42-8.83), fasting blood glucose (OR = 1.139; 95% CI: 1.054-1.231), blood glucose 2 hours after breakfast (OR = 1.088; 95% CI: 1.028-1.152), systolic blood pressure (OR = 1.049; 95% CI: 1.030-1.069) and diastolic blood pressure (OR = 1.061; 95% CI: 1.026-1.097) had significant association with nephropathy.Conclusion: HbA1c categories >7.0% is an important risk factor for the development of nephropathy.KYAMC Journal Vol. 8, No.-1, Jul 2017, Page 21-26

scholarly journals SRT1720 retards renal fibrosis via inhibition of HIF1A/GLUT1 in diabetic nephropathy

2019 ◽  
Vol 241 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Weixia Han ◽  
Chen Wang ◽  
Zhifen Yang ◽  
Lin Mu ◽  
Ming Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Collagen Iv ◽  
Protective Effects ◽  
Sirt1 Expression ◽  
Mesenchymal Transformation

Renal fibrosis is the major pathological characteristic of diabetic nephropathy (DN). Reportedly, increased SIRT1 expression played a renal protective role in animal models of DN. This study was designed to elucidate the molecular mechanisms underlying the protective effects of SRT1720, an SIRT1 activator, against diabetes-induced renal fibrosis. Type 2 diabetic mice (db/db) were treated with SRT1720 (50 mg/kg/day) by gavage for 10 weeks. Renal proximal tubular epithelial cells (HK-2 cells) were treated with high glucose (HG, 30 mM) in the presence or absence of SRT1720 (2.5 µM) for 48 h. We observed that impaired SIRT1 expression and activity were restored by SRT1720 administration in db/db mice as well as in HG-treated HK-2 cells. Moreover, SRT1720 administration improved the renal function, attenuated glomerular hypertrophy, mesangial expansion, glomerulosclerosis and interstitial fibrosis and inhibited TGFB1 and CTGF expressions and nuclear factor κB (NF-KB) activation in db/db mice. Similarly, HG-induced epithelial-to-mesenchymal transformation (EMT) and collagen IV and fibronectin expressions were inhibited in SRT1720-treated HK-2 cells. Mechanistic studies demonstrated that SRT1720 suppressed HIF1A, GLUT1 and SNAIL expressions both in vivo and in vitro. Furthermore, HIF1A or GLUT1 knockdown effectively abrogated HG-induced EMT and collagen IV and fibronectin expressions in HK-2 cells. These findings suggest that SRT1720 prevented diabetes-induced renal fibrosis via the SIRT1/HIF1A/GLUT1/SNAIL pathway.

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