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

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 ß1 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.

Exendin-4 is effective against metabolic disorders induced by intrauterine and postnatal overnutrition in rodents.

AIMS/HYPOTHESIS: Maternal obesity leads to increased adiposity, hyperlipidaemia and glucose intolerance in offspring. The analogue of glucagon-like peptide-1, exendin-4 (Ex-4), has been shown to induce weight loss in both adolescence and adulthood. We hypothesised that, in rats, daily injection of Ex-4 would reduce body fat and improve metabolic disorders in offspring from obese dams, especially those consuming a high-fat diet (HFD). METHODS: Female Sprague Dawley rats were fed chow or an HFD for 5 weeks before mating, and throughout gestation and lactation. At postnatal day 20, male pups from HFD-fed mothers were weaned onto chow or HFD and those from chow-fed mothers were fed chow. Within each dietary group, half of the pups were injected with Ex-4 (15 µg/kg/day i.p.) for 6 weeks, while the other half received saline. RESULTS: Maternal obesity alone or combined with postweaning HFD consumption led to increased adiposity, hyperinsulinaemia, hyperlipidaemia, inflammation and impaired regulation of hypothalamic appetite regulators by glucose in offspring, while glucose intolerance was only observed in HFD-fed rats from obese dams. Ex-4 injection significantly reduced adiposity, hyperlipidaemia and insulin resistance in HFD-fed rats from obese dams. It also restored glucose tolerance and the lipid-lowering effect of blood glucose. However, Ex-4 did not change hypothalamic appetite regulation or the response of appetite regulators to hyperglycaemia. Liver and adipose inflammatory cytokine expression was significantly reduced by Ex-4. CONCLUSIONS/INTERPRETATION: Ex-4 reversed the detrimental impact of maternal obesity on lipid and glucose metabolism in offspring regardless of diet, supporting its potential application in reducing metabolic disorders in high-risk populations.

Combined Effects of PPAR γ Agonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells.

We aimed to determine whether epidermal growth factor receptor (EGFR) inhibition, in addition to a peroxisome proliferator-activated receptor gamma (PPAR γ ) agonist, prevents high-glucose-induced proximal tubular fibrosis, inflammation, and sodium and water retention in human proximal tubule cells exposed to normal glucose; high glucose; high glucose with the PPAR γ agonist pioglitazone or with the P-EGFR inhibitor, gefitinib; or high glucose with both pioglitazone and gefitinib. We have shown that high glucose increases AP-1 and NF κ B binding activity, downstream phosphorylation of EGFR and Erk1/2, and fibronectin and collagen IV expression. Pioglitazone reversed these effects but upregulated NHE3 and AQP1 expression. Gefitinib inhibited high glucose induced fibronectin and collagen IV, and EGFR and Erk1/2 phosphorylation and reversed pioglitazone-induced increases in NHE3 and AQP1 expression. Our data suggests that combination of an EGFR inhibitor and a PPAR γ agonist mitigates high-glucose-induced fibrosis and inflammation and reverses the upregulation of transporters and channels involved in sodium and water retention in human proximal tubule cells. Hence EGFR blockade may hold promise, not only in limiting tubulointerstitial pathology in diabetic nephropathy, but also in limiting the sodium and water retention observed in patients with diabetes and exacerbated by PPAR γ agonists.