title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  Peroxisome proliferator-activated receptor (PPAR)-α/γ 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 PPARα/γ and investigated its anti-DN effects in a DN rat model.
  
  
  METHODS
  ChIP and reporter gene assays were performed and the expression of PPARα/γ target genes was monitored to examine the ability of HKC to activate PPARα/γ. 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 (300mg/kg/d); middle dose HKC (175mg/kg/d); and low dose HKC (75mg/kg/d). Irbesartan (4mg/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, TGFβ, TNFα 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 PPARα and PPARγ 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 PPARα/γ 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.
authors.affiliation: Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ge
authors.affiliation: Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China.
authors.forename: Jun-Jun
authors.initials: JJ
authors.lastname: Miao
authors.affiliation: Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China.
authors.forename: Xin-Yi
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Jiangsu Province Hosipital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing Hanzhong Road, Nanjing, China. Electronic address: jiangyiyunjcm@sohu.com.
authors.forename: Jiang-Yi
authors.initials: JY
authors.lastname: Yu
mesh_terms: D028483:Abelmoschus / Q000737:chemistry*; D000284:Administration, Oral; D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002214:Capsules; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000378:metabolism / Q000517:prevention & control; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000077405:Irbesartan; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D013777:Tetrazoles / Q000494:pharmacology; D014162:Transfection
chemical_list: D001713:Biphenyl Compounds; D002214:Capsules; D004365:Drugs, Chinese Herbal; D008055:Lipids; D047493:PPAR alpha; D047495:PPAR gamma; D010936:Plant Extracts; D013777:Tetrazoles; D013311:Streptozocin; D000077405:Irbesartan
keywords: Diabetic nephropathy; Endoplasmic reticulum stress; Fenofibrate (PubChem CID: 3339); Huangkui capsule; Irbesartan (PubChem CID: 3749); PPARα/γ; Streptozocin (PubChem CID: 29327); Thapsigargin (PubChem CID: 446378); Troglitazone (PubChem CID: 5591)