Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating peroxisome proliferator-activated receptor (PPAR)-α/γ and attenuating endoplasmic reticulum stress in rats

Ethnopharmacological relevance: Abelmoschus manihot (L.) medic (AM) is a natural medicinal plant used for the treatment of chronic kidney disease (CKD) in China. Huangkui capsule (HKC), an extract from AM, has been proved clinically effective in improving renal inflammation and glomerular injury in CKD. However, the mechanisms of HKC are still not fully understood. Aim of the study: Peroxisome proliferator activated receptor (PPAR)-alpha/gamma dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes and diabetic nephropathy (DN). This study evaluated the function of Huangkui capsule (HKC), an extract from Abelmoschus manihot (L) medic (AM), as a dual agonist for PPAR alpha/gamma and investigated its anti-DN effects in a DN rat model. Materials and methods: ChIP and reporter gene assays were performed and the expression of PPAR alpha/gamma target genes was monitored to examine the ability of HKC to activate PPAR alpha/gamma. DN was induced in male Sprague Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin. HKC was administered to the diabetic nephropathy rats at three different doses: high dose HKC (300 mg/kg/d); middle dose HKC (175 mg/kg/d); and low dose HKC (75 mg/kg/d). Irbesartan (4 mg/kg/d body weight) was used as a positive control. Following 12 weeks' treatment, we measured general status, renal morphological appearance, proteinuria, blood biochemical parameters, and glomerular morphological changes. The expression of collagen IV, TGF beta, TNF alpha and IL-6 in renal tissue was evaluated. Endoplasmic reticulum (ER) stress in renal tissue was also analyzed. Results: HKC enhanced the transcriptional activity of PPAR alpha and PPAR gamma in cultured cells, livers and kidneys of DN rats, and it reduced serum triglyceride and cholesterol levels and fat in livers of DN rats. Furthermore, HKC reduced the expressions of inflammatory genes in kidneys of DN rats. Strikingly, HKC reduced ER stress and c-Jun NH2-terminal kinase activation in the liver and kidney of DN rats and subsequently improved renal injury. Conclusions: Our results show that HKC improved lipid metabolic disorders by activating PPAR alpha/gamma and attenuating ER stress. HKC could dose-dependently ameliorate renal inflammation and glomerular injury in DN rats. These results suggest that HKC has potential as an anti-DN agent for the treatment of DN in humans. (C) 2016 Elsevier Ireland Ltd. All rights reserved.