Abstract
Diabetic nephropathy (DN) is a common and severe complication of diabetes, impacting millions of people worldwide. High concentrations of serum glucose-associated injury of renal glomerular endothelial cells (rGECs) are involved in the DN pathogenesis. We found that exposure to high glucose increased the expression of angiotensin II type 1 receptor (AT1R) in human rGECs (hrGECs). To block the increased AT1R level, we used the newly developed antagonist Telmisartan. This study investigated whether Telmisartan possessed a beneficial effect against high-glucose-induced insults in hrGECs and explored the underlying mechanism. Our findings indicate that Telmisartan ameliorated high-glucose-induced mitochondrial dysfunction by increasing mitochondrial membrane potential. Also, Telmisartan attenuated oxidative stress by reducing the levels of two oxidative stress biomarkers 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA). Further, we found that Telmisartan prevented high-glucose-induced expression of NADPH oxidase 2 (NOX-2). Interestingly, exposure to high glucose resulted in the increased endothelial permeability of renal glomerular endothelial cells, which was mitigated by treatment with Telmisartan. Mechanistically, these effects are mediated by the MLCK/MLC-2/occludin signaling pathway. In the leptin-deficient db/db diabetic mouse model, we proved that Telmisartan treatment ameliorated the reduction of occludin and albuminuria. In conclusion, our findings demonstrate that Telmisartan possesses protective effects on high-glucose-induced injury to renal glomerular endothelial cells; its antagonizing of AT1R could be a potential therapeutic target in diabetic nephropathy.
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