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.