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Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

ABSTRACT: BACKGROUND AND OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect. RESEARCH DESIGN AND METHODS: We induced diabetes using a low dose streptozotocin protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice). RESULTS: Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor ?1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups. CONCLUSION: Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

SUBMITTER: Gangadharan Komala M

PROVIDER: S-EPMC4219667 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

Gangadharan Komala Muralikrishna M Gross Simon S Mudaliar Harshini H Huang Chunling C Pegg Katherine K Mather Amanda A Shen Sylvie S Pollock Carol A CA Panchapakesan Usha U

PloS one 20141104 11

<h4>Background and objective</h4>Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its ...[more]

PMID: 25369239

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Project description:Background and objectivesThe estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure.Design, setting, participants, & measurementsWe established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance.ResultsLow TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P<0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change.ConclusionsTmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.

Dataset Information

Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

Publications

Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

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