Quercetin inhibited mesangial cell proliferation of early diabetic nephropathy through the Hippo pathway

Abstract

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and the leading cause of end-stage renal disease. The proliferation of glomerular mesangial cells (MCs) is a common and prominent pathological change of DN, which takes place at the early stage. Quercetin, a bioflavonoid compound, possesses therapeutic efficacy in cardiovascular and kidney diseases via anti-tumour, anti-oxidation, anti-virus, and anti-proliferation effects. However, the mechanism of quercetin in the proliferation of glomerular MCs in early DN has not been reported. In the present study, we investigated the effect of quercetin on the proliferation of glomerular MCs in high glucose-induced mouse glomerular MCs and in db/db mice. On this basis, we tried to clarify the specific mechanisms underlying these effects. The in vitro results showed that the proliferation of glomerular MCs was induced by high glucose, and the Hippo pathway was highly inactivated in high glucose-cultured MCs. Decreased phosphorylation of MST1 and Lats1 promoted expression and nuclear translocation of Yes-associated protein (YAP) and subsequently increased the combination of YAP and TEA/ATS domain (TEAD), which promoted the expression of the downstream target gene such as cyclinE. Quercetin effectively inhibited the high glucose-induced MC proliferation and reactivated the Hippo pathway. In vivo, the proliferation of glomerular MCs was increased, renal function was decreased, and blood fasting glucose was elevated in db/db mice. Furthermore, the Hippo pathway was inactivated in the renal cortex of db/db mice. Eight-week treatment of quercetin retarded MC proliferation, alleviated the renal function, and reactivated Hippo pathway in the renal cortex of db/db mice at 16 weeks. Our previous study clarified that the Hippo pathway was involved in MC proliferation of DN. The results revealed that quercetin inhibited MC proliferation in high glucose-treated mouse glomerular MCs and in DN via reactivation of the Hippo pathway.

Keywords: Diabetic nephropathy; Hippo pathway; Mesangial cells; Proliferation; Quercetin.