SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway.

Abstract

During diabetic kidney disease (DKD), tubulointerstitial fibrosis persists, although several methods have been applied to reduce albuminuria levels. In this research, we found that bovine serum albumin (BSA)-induced renal tubular cell injury could also spread to normal tubular cells through exosomes, which may explain why tubulointerstitial fibrosis persists. Our previous studies revealed that SESN2 overexpression alleviates tubular dysfunction. In this study, we showed that SESN2 overexpression in donor HK2 cells interrupted this "doom loop" and confirmed that SESN2 may mediate this process by reducing exosome secretion. By using RNA-seq and IP-MS, we found that SESN2 could inhibit BSA-induced Rab-7a ubiquitination, thus promoting autophagosome and lysosome fusion and accelerating MVB degradation. We also showed that SESN2 promotes the nuclear translocation of TFEB through the mTOR pathway, thus further alleviating lysosomal function and promoting MVB degradation. We also found that SESN2 not only slowed DKD progression but also promoted renal tubular cell secretion of protective exosomes, which also slowed DKD progression. In conclusion, SESN2 can interrupt the progression of albuminuria-induced tubular injury by inhibiting exosome secretion and promoting MVB degradation. Thus, SESN2 may be a new therapeutic target for DKD treatment.