Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy

• Published in: Molecular and cellular endocrinology 2023-06, Vol.568-569, p.111913-111913, Article 111913
• Main Authors: Ding, Lin, Li, Zuo-lin, Zhou, Yan, Liu, Nan-chi, Liu, Shan-shan, Zhang, Xing-jian, Liu, Cong-cong, Zhang, Dong-jie, Wang, Gui-hua, Ma, Rui-xia
• Format: Article
• Language: English
• Subjects: ATP6V1A; Diabetes Mellitus - metabolism; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Exosome secretion; Exosomes - metabolism; Humans; Hydrogen-Ion Concentration; Lysosomes - metabolism; Podocyte; Podocytes - metabolism; Sirt1; Sirtuin 1 - metabolism
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2023.111913

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. •Reduced fusion of MVBs with lysosomes and increased exosome release in DN podocytes.•Sirt1 was decreased in DN podocytes, and its overexpression inhibited podocyte exosome secretion in DN.•Sirt1 improved lysosomal acidification with increased expression of ATP6V1A and inhibited exosome secretion in DN podocytes.