Impact of induction of autophagy by rapamycin with or without metformin on the clinical and pathological aspects of diabetic nephropathy in rats

Emad Samaan, Samar Ahmed, Hussein Sheashaa, DinaAbdallah Ibrahim, Nagy Sayed-Ahmed
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Abstract

Background The induction of autophagy by synergistic activation of mTORC1 and reduction of AMPK may be a novel therapeutic option for suppressing diabetic nephropathy (DN) progression. Materials and Methods Forty-eight adult male Sprague Dawley rats were studied for 10 weeks. The rats were randomly divided into a healthy control group (n=12) and 3 induced diabetic groups (n=12 each); the groups were either non-treated, treated with rapamycin, or treated with both rapamycin and metformin. At a set time of 3 weeks, 6 weeks, and 10 weeks urinary albumin ration as well as serum creatinine were obtained, and at least three rats were sacrificed. We used immunohistochemical staining of kidney tissue to study autophagy with LC3 antibody. We relied on Electron microscopy to measure GBM thickening and the degree of mesangial expansion. Results Compared to non-treated rats, diabetic rats treated with rapamycin alone or rapamycin and metformin showed a lower level of proteinuria and almost normal serum creatinine through all study intervals. Also, the histopathological analysis showed increased expression of LC3 in both treated and non-treated diabetic rat groups. There were no significant differences between both treated groups in levels of LC3 expression. At week 10, the mesangial expansion score was less in rats on combination therapy than in rats treated only with rapamycin. Conclusion Autophagy induction in DN ameliorates the clinical and pathological severity. Adding metformin to rapamycin seems to be of benefit in halting the pathological progression.
雷帕霉素联合或不联合二甲双胍诱导自噬对糖尿病肾病大鼠临床和病理的影响
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