Abstract
Huangkui capsule (HKC), a Chinese modern patent medicine extracted from Abelmoschus manihot (L.) medic, has been widely applied to clinical therapy in the early diabetic nephropathy (DN) patients. However, it remains elusive whether HKC can ameliorate the inchoate glomerular injuries in hyperglycemia. Recently the activation of phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling and its downstream regulator, 70-kDa ribosomal protein S6 kinase (p70S6K), play important roles in the early glomerular pathological changes of DN including glomerular hypertrophy, glomerular basement membrane (GBM) thickening and mild mesangial expansion. This study thereby aimed to clarify therapeutic effects of HKC during the initial phase of DN and its underlying mechanisms. Fifteen rats were randomly divided into 3 groups: the normal group, the model group and the HKC group. The early DN model rats were induced by unilateral nephrectomy combined with intraperitoneal injection of streptozotocin, and administered with either HKC suspension or vehicle after modeling and for a period of 4 weeks. Changes in the incipient glomerular lesions-related parameters in urine and blood were analyzed. Kidneys were isolated for histomorphometry, immunohistochemistry, immunofluorescence and Western blotting (WB) at sacrifice. In vitro, murine mesangial cells (MCs) were used to investigate inhibitory actions of hyperoside (HYP), a bioactive component of HKC, on cellular hypertrophy-associated signaling pathway by WB, compared with rapamycin (RAP). For the early DN model rats, HKC ameliorated micro-urinary albumin, body weight and serum albumin, but had no significant effects on renal function and liver enzymes; HKC improved renal shape, kidney weight and kidney hypertrophy index; HKC attenuated glomerular hypertrophy, GBM thickening and mild mesangial expansion; HKC inhibited the phosphorylation of Akt, mTOR and p70S6K, and the protein over-expression of transforming growth factor-β1 in kidneys. In vitro, the phosphorylation of PI3K, Akt, mTOR and p70S6K in MCs induced by high-glucose was abrogated by treatment of HYP or RAP. On the whole, this study further demonstrated HKC safely and efficiently alleviates the early glomerular pathological changes of DN, likely by inhibiting Akt/mTOR/p70S6K signaling activity in vivo and in vitro, and provided the first evidence that HKC directly contributes to the prevention of the early DN.
Highlights
The early diabetic nephropathy (DN) in both animal models and humans is characterized histologically by glomerular hypertrophy, glomerular basement membrane (GBM) thickening and mild mesangial expansion (Tervaert et al, 2010; Najafian et al, 2011)
The significant improvement in foot process loss and effacement and nephrin protein expression in the kidneys of the Huangkui capsule (HKC) group rats was not found. These results indicated that HKC could ameliorate glomerular pathological changes of the early DN model rats, such as glomerular hypertrophy, GBM thickening and mild mesangial expansion
In the present study, using a modified DN rat model and the murine mesangial cells (MCs), we emphatically demonstrated that HKC at the safe and effective dose of 2 g/kg/day can improve micro-UAlb and renal enlargement and alleviate the early glomerular pathological changes including glomerular hypertrophy, GBM thickening and mild mesangial expansion, and that, more importantly, these ameliorative effects are closely related with the inhibition of serine-threonine kinase (Akt)/Mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) signaling activity in vivo and in vitro
Summary
The early diabetic nephropathy (DN) in both animal models and humans is characterized histologically by glomerular hypertrophy, glomerular basement membrane (GBM) thickening and mild mesangial expansion (Tervaert et al, 2010; Najafian et al, 2011). Angiotensin-converting enzyme inhibitors, angiotensin receptor blocker (Tuttle et al, 2014; Glassock, 2016) and some newly discovered drugs including glucagons-like peptide 1 agonists (Muskiet et al, 2017), dipeptidyl peptidase 4 inhibitors (Penno et al, 2016), sodiumglucose cotransporter 2 inhibitors (Zinman et al, 2015; Wanner et al, 2016) may help and treat the early DN patients by allowing tighter safer control of blood glucose level and by exerting beneficial direct effects on renal injuries, it is still unclear whether they can ameliorate the inchoate glomerular pathological changes including hypertrophic glomerulus, thickened GBM and mild mesangial expansion. Targeting the activation of PI3K/Akt/mTOR signaling and the expression of phosphorylated p70S6K (pp70S6K) in the kidneys could be therapeutic mechanisms for ameliorating the early glomerular lesions of DN
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