ODP200 Fyn is involved in the development of diabetic kidney disease by modulating autophagy

Abstract

Abstract Diabetic kidney disease (DKD) is one of the major diabetic complications and the leading cause of the end stage renal disease. Recently autophagy was shown to regulate DKD. Previously we reported that Fyn regulates muscle mass by suppressing autophagy through Fyn-STAT3 signaling pathway. More recently, we demonstrated that Fyn also inhibits autophagy in HK2 cells, in vitro cell model of renal proximal tubular epithelial cells (RPTC). Moreover, we found Y369 of Tgm2, a known inhibitor of autophagy, is directory phosphorylated by Fyn both in vitro and in cells and Fyn-dependent phosphorylation of Tgm2 regulates autophagy in RPTC. It has been reported that Tgm2 forms complexes with p53 and p62 (a known autophagy regulator) to mediate the degradation of p53 at autophagosomes in cancer cells. To note is that p53 could function as a DKD inducer. We found that p53 expression was decreased in Tgm2 knock-downed HK2 cells, suggesting that Tgm2-p62-p53 complex also modulates autophagy in RPTC. Since these were only in vitro studies, we proceeded with those in vivo. In HFD fed mice, diet-induced rodent models of metabolic disorders, we found that protein expression of p53 was increased due to decreased levels of autophagy implicated by decreased p62 punctuations in RPTC. To confirm the role of Fyn in autophagy and p53 expression we took advantage of a diabetic mouse model of FynKO mice induced by Streptozocin(STZ). While p53 was increased in the kidney of diabetic WT mice induced by STZ, it was not the case in the kidney of diabetic FynKO, indicating that Fyn could regulate autophagic activity and p53 expression. Taken together, these data suggest that the metabolic status may regulate Fyn to phosphorylate Tgm2 and modulate Tgm2-p62-p53 complex leading to the development of DKD. This regulatory mechanism is not mediated by blood glucose and may lead to the new therapeutic targets for diabetic kidney disease regardless of control of diabetes. Presentation: No date and time listed