title: Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance.
abstract: Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined. Hibiscus sabdariffa polyphenols (HPE) inhibited high glucose-induced angiotensin II receptor-1 (AT-1), thus attenuating renal epithelial mesenchymal transition (EMT). Recently, we reported HPE inhibited dipeptidyl-peptidase-4 (DPP-4, the enzyme degrades type 1 glucagon-like peptide (GLP-1)), which mediated insulin resistance signals leading to EMT. Since free fatty acids can realistically bring about insulin resistance, using the palmitate-stimulated cell model in contrast with type 2 diabetic rats, in this study we examined if insulin resistance causes renal EMT, and the preventive effect of HPE. Our findings reveal that palmitate hindered 30% of glucose uptake. Treatment with 1 mg mL(-1) of HPE and the DPP-4 inhibitor linagliptin completely recovered insulin sensitivity and palmitate-induced signal cascades. HPE inhibited DPP-4 activity without altering the levels of DPP-4 and the GLP-1 receptor (GLP-1R). HPE decreased palmitate-induced phosphorylation of Ser307 of insulin receptor substrate-1 (pIRS-1 (S307)), AT-1 and vimentin, while increasing phosphorylation of phosphatidylinositol 3-kinase (pPI3K). IRS-1 knockdown revealed its essential role in mediating downstream AT-1 and EMT. In type 2 diabetic rats, it suggests that HPE concomitantly decreased the protein levels of DPP-4, AT-1, vimentin, and fibronectin, but reversed the in vivo compensation of GLP-1R. In conclusion, HPE improves insulin sensitivity by attenuating DPP-4 and the downstream signals, thus decreasing AT-1-mediated tubular-interstitial EMT. HPE could be an adjuvant to prevent diabetic nephropathy.
authors.affiliation: Department of Internal Medicine, Chung-Shan Medical University Hospital, Number 110, Section 1, Chien-Kuo North Road, Taichung 402, Taiwan and Institute of Medicine, Chung-Shan Medical University, Number 110, Section 1, Chien-Kuo North Road, Taichung 402, Taiwan.
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Huang
authors.affiliation: Institute of Biochemistry and Biotechnology, Chung-Shan Medical University, Number 110, Section 1, Chien-Kuo North Road, Taichung 402, Taiwan.
authors.forename: Chau-Jong
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Chung-Shan Medical University Hospital, Number 110, Section 1, Chien-Kuo North Road, Taichung 402, Taiwan.
authors.forename: Yi-Sun
authors.initials: YS
authors.lastname: Yang
authors.affiliation: Institute of Medicine, Chung-Shan Medical University, Number 110, Section 1, Chien-Kuo North Road, Taichung 402, Taiwan.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Division of Basic Medical Science, Hungkuang University, No. 1018, Sec. 6, Taiwan Boulevard, Shalu District, Taichung City 43302, Taiwan. a222907@sunrise.hk.edu.tw.
authors.forename: Chiung-Huei
authors.initials: CH
authors.lastname: Peng
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D031584:Hibiscus / Q000737:chemistry*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007668:Kidney; D000069476:Linagliptin; D059630:Mesenchymal Stem Cells; D010168:Palmitates / Q000633:toxicity*; D059808:Polyphenols / Q000737:chemistry*; D051381:Rats; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010168:Palmitates; D059808:Polyphenols; D014746:Vimentin; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4