The following is a summary of “Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy,” published in the June 2023 issue of Molecular and Cellular Endocrinology by Ding et al.

Podocyte damage is a defining characteristic of diabetic nephropathy (DN). The secretion of exosomes by podocytes is significantly increased in DN; however, the exact mechanisms remain inadequately understood. In this study, the researchers demonstrated that Sirtuin1 (Sirt1) was substantially downregulated in podocytes of diabetic nephropathy (DN), which negatively correlated with increased exosome secretion. 

In vitro, identical results were observed. Following high glucose administration, lysosomal acidification in podocytes was significantly inhibited, resulting in decreased lysosomal degradation of multivesicular bodies. Loss of Sirt1 inhibited lysosomal acidification by reducing expression of the A subunit of the lysosomal vacuolar-type H⁺ ATPase proton pump (ATP6V1A) in podocytes. Sirt1 overexpression significantly improved lysosomal acidification by increasing ATP6V1A expression and inhibiting exosome secretion. 

These findings suggest that dysfunctional Sirt1-mediated lysosomal acidification is the precise mechanism of increased exosome secretion in podocytes in DN, thereby shedding light on potential therapeutic strategies for halting the progression of DN.

Source: sciencedirect.com/science/article/abs/pii/S0303720723000643