Kaempferol attenuated diabetic nephropathy by reducing apoptosis and promoting autophagy through AMPK/mTOR pathways

Abstract

IntroductionRenal podocyte injury, apoptosis and autophagy are involved in the occurrence and development of diabetic nephropathy (DN). Kaempferol (KPF) has the promotion of autophagy and inhibition of apoptosis properties in the development of miscellaneous diseases, but these functions in DN have not yet been elucidated.MethodsWe used db/db mice to evaluate the protective role of KPF on DN. The anti-DN effect of KPF was evaluated by urine albumin-to-creatinine ratio and pathological changes of kidney tissue. Injury of podocytes was observed through Transmission electron microscopy. Immunofluorescence, Western blot, and Immunohistochemistry were used to detect the protein expression of podocyte-associated molecules, autophagy, and AMPK/mTOR pathway.ResultsWe demonstrated that KPF treatment significantly attenuated diabetes-induced albuminuria and glycolipid metabolism dysfunction. In addition, KPF alleviated mesangial matrix expansion, glomerular basement membrane thickening and loss or fusion of podocytes. Mechanistically, KPF treatment regulated the expression of autophagic proteins (upregulated LC3II, Beclin-1, Atg7 and Atg 5, and downregulated p62/SQSTM1), accompanied by inhibited renal apoptosis (downregulated Caspase 3 and Bax, and upregulated Bcl-2). KPF could significantly regulate the AMPK/mTOR signaling pathways by increasing p-AMPK and decreasing p-mTOR expressions.DiscussionIn conclusion, KPF might have a protective effect on DN through reduced apoptosis and enhanced podocytes autophagy, which were correlated with regulating AMPK/mTOR pathways.

Exploration of the possible mechanisms of Ling Gui Zhu Gan decoction in nephrotic syndrome based on network pharmacology, molecular docking and molecular dynamics simulation

“…[28][29][30][31] Kaempferol has been demonstrate to reduce mesangial matrix expansion, glomerular basement membrane and podocyte loss by inhibiting apoptosis and promoting autophagy through AMPK/mTOR pathways, thereby protecting the kidney. [32] It was found that Astragalus membranaceus could inhibit renal fibrosis and inflammation, as well as reduce blood creatinine and cystatin, thus playing a protective role in the kidney. [33,34] Moreover, studies have shown that naringenin may inhibit the expression of inflammatory cells, attenuate oxidative stress and the accumulation of extracellular matrix in the glomerulus, exhibiting renal protective effect.…”

The role of autophagy in insulin resistance and glucolipid metabolism and potential use of autophagy modulating natural products in the treatment of type 2 diabetes mellitus

“…178,179 Additionally, kaempferol exhibits a capacity to alleviate renal histological and functional damage in db/db mice. 145 Kaempferol treatment leads to a decrease in the urine albumin-to-creatinine ratio and reduces the accumulation of extracellular matrix. The stimulation of autophagy through the activation of AMPK and inhibition of mTOR is suggested to be a contributor for these beneficial effects of kaempferol.…”

“…The antidiabetic activity of kaempferol has been indicated in HFD‐induced diabetic mice 178,179 . Additionally, kaempferol exhibits a capacity to alleviate renal histological and functional damage in db / db mice 145 . Kaempferol treatment leads to a decrease in the urine albumin‐to‐creatinine ratio and reduces the accumulation of extracellular matrix.…”

Targeting autophagy with natural products as a potential therapeutic approach for diabetic microangiopathy

“…It alleviates mesangial matrix expansion and podocyte loss or fusion in DKD. It slows DKD progression by upregulating podocyte autophagy via the AMPK/mTOR pathway, evidenced by increased LC3II, Beclin-1, p-AMPK, Bcl-2, Atg7, and Atg5, and decreased p-mTOR, Bax, caspase-3, and p62 expression ( Sheng et al, 2022 ). Mangiferin and phenolics from Physalis peruviana fruits have both been shown to exert a protective effect on the kidney by enhancing autophagy through the AMPK/mTOR pathway ( Wang X. et al, 2018 ; Ezzat et al, 2021 ).…”