title: Metformin ameliorates lipotoxicity-induced mesangial cell apoptosis partly via upregulation of glucagon like peptide-1 receptor (GLP-1R).
abstract: Glucagon like peptide-1 receptor (GLP-1R), known to be expressed in pancreatic beta cells, is also expressed in glomerular mesangial cells and its agonist has protective effects in diabetic nephropathy. However, its regulatory mechanisms by lipotoxicity in glomerular mesangial cells are not understood. We found that palmitate-mediated lipotoxicity increased apoptosis and decreased GLP-1R expression in a rat mesangial cell line. Silencing GLP-1R expression also increased mesangial cell apoptosis. Interestingly, metformin, one of the biguanide drugs that has anti-diabetic effects, attenuated lipotoxicity-induced mesangial cell apoptosis and restored GLP-1R expression. Moreover, this treatment alleviated GLP-1R knockdown-induced mesangial cell apoptosis. To further evaluate in vivo, diabetic obese db/db mice were administered metformin. Glomerular GLP-1R expression was diminished in db/db mice, as compared with db/m control mice. However, this decrease significantly recovered on metformin administration. Together, these data provide novel evidence that lipotoxicity decreases the mesangial GLP-1R expression in intact cells and in vivo. The decrease induced mesangial cell apoptosis. Furthermore, we provided the evidence that metformin treatment has a renal protective effect partly via increased mesangial GLP-1R expression. Our data suggested that regulation of GLP-1R expression could be a promising approach to treat diabetic nephropathy and the novel mechanism of metformin mediated GLP-1R regulation.
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea; Life Science Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: dongil@umich.edu.
authors: Dong-il
authors: DI
authors: Kim
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea; Departments of Molecular & Integrative Physiology and Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Min-jung
authors: MJ
authors: Park
authors: Department of Food and Nutrition, Chonnam National University, Gwangju 500-757, South Korea.
authors: Young-ran
authors: YR
authors: Heo
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea. Electronic address: parksh@chonnam.ac.kr.
authors: Soo-hyun
authors: SH
authors: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000096:biosynthesis* / Q000235:genetics; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D008687:Metformin
keywords: Apoptosis; GLP-1R; Glucagon like peptide-1 receptor; Mesangial cell; Metformin; Palmitate