Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy
Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy
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DOI：
10.1016/j.mce.2023.111913
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发表时间：
2023-03
影响因子：
4.1
通讯作者：
Lin Ding;Zuo-Lin Li;Yan Zhou;Nan-chi Liu;Shan-shan Liu;Xing-jian Zhang;Cong-cong Liu;Dong-jie Zhang;Gui-Hua Wang;R. Ma
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文献类型：
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作者：
Lin Ding;Zuo-Lin Li;Yan Zhou;Nan-chi Liu;Shan-shan Liu;Xing-jian Zhang;Cong-cong Liu;Dong-jie Zhang;Gui-Hua Wang;R. Ma
足细胞损伤是糖尿病肾病（DN）的特征性特征。足细胞外泌体的分泌在DN中显著增加;然而，确切的机制仍然知之甚少。在这里，我们证明了Sirtuin 1（Sirt 1）在DN足细胞中显著下调，这与外泌体分泌增加呈负相关。在体外观察到类似的结果。我们发现，高葡萄糖给药后，足细胞中的溶酶体酸化被明显抑制，导致多泡体的溶酶体降解减少。从机制上讲，我们表明Sirt 1的缺失通过降低足细胞中溶酶体空泡型H+ ATP酶质子泵（ATP 6V 1A）的A亚基的表达来抑制溶酶体酸化。Sirt 1的过表达显著改善了溶酶体酸化，增加了ATP 6V 1A的表达，并抑制了外泌体分泌。这些发现表明，功能失调的Sirt 1介导的溶酶体酸化是DN足细胞外泌体分泌增加的确切机制，为预防DN进展提供了潜在的治疗策略。
Podocyte injury is a characteristic feature of diabetic nephropathy (DN). The secretion of exosomes in podocytes increases significantly in DN; however, the precise mechanisms remain poorly understood. Here, we demonstrated that Sirtuin1 (Sirt1) was significantly downregulated in podocytes in DN, which correlated negatively with increased exosome secretion. Similar results were observed in vitro. We found that lysosomal acidification in podocytes following high glucose administration was markedly inhibited, resulting in the decreased lysosomal degradation of multivesicular bodies. Mechanistically, we indicated that loss of Sirt1 contributed to the inhibited lysosomal acidification by decreasing the expression of the A subunit of the lysosomal vacuolar-type H+ATPase proton pump (ATP6V1A) in podocytes. Overexpression of Sirt1 significantly improved lysosomal acidification with increased expression of ATP6V1A and inhibited exosome secretion. These findings suggest that dysfunctional Sirt1-mediated lysosomal acidification is the exact mechanism of increased secretion of exosomes in podocytes in DN, providing insights into potential therapeutic strategies for preventing DN progression.