Sestrin2 attenuates renal damage by regulating Hippo pathway in diabetic nephropathy

Glomerular mesangial cell proliferation and extracellular matrix accumulation contribute to the progression of diabetic nephropathy (DN). As a conserved stress-inducible protein, sestrin2 (Sesn2) plays critical role in the regulation of oxidative stress, inflammation, autophagy, metabolism, and endoplasmic reticulum stress. In this study, we investigated the role of Sesn2 on renal damage in diabetic kidney using transgenic mice overexpressing Sesn2 and the effect of Sesn2 on mesangial cell proliferation and extracellular matrix accumulation in diabetic conditions and the possible molecular mechanisms involved. Sesn2 overexpression improved renal function and decreased glomerular hypertrophy, albuminuria, mesangial expansion, extracellular matrix accumulation, and TGF-β1 expression, as well as oxidative stress in diabetic mice. In vitro experiments, using human mesangial cells (HMCs), revealed that Sesn2 overexpression inhibited high glucose (HG)-induced proliferation, fibronectin and collagen IV production, and ROS generation. Meanwhile, Sesn2 overexpression restored phosphorylation levels of Lats1 and YAP and inhibited TEAD1 expression. Inhibition of Lats1 accelerated HG-induced proliferation and expression of fibronectin and collagen IV. Verteporfin, an inhibitor of YAP, suppressed HG-induced proliferation and expression of fibronectin and collagen IV. However, Sesn2 overexpression reversed Lats1 deficiency-induced Lats1 and YAP phosphorylation, nuclear expression levels of YAP and TEAD1, and proliferation and fibronectin and collagen IV expressions in HMCs exposed to HG. In addition, antioxidant NAC or tempol treatment promoted phosphorylation of Lats1 and YAP and inhibited TEAD1 expression, proliferation, and fibronectin and collagen IV accumulation in HG-treated HMCs. Taken together, Sesn2 overexpression inhibited mesangial cell proliferation and fibrosis via regulating Hippo pathway in diabetic nephropathy. Induction of Sesn2 may be a potential therapeutic target in diabetic nephropathy.