title: 12-Lipoxygenase Inhibition on Microalbuminuria in Type-1 and Type-2 Diabetes Is Associated with Changes of Glomerular Angiotensin II Type 1 Receptor Related to Insulin Resistance.
abstract: (1) BACKGROUND: 12-lipoxygenase (12-LO) is involved in the development of diabetic nephropathy (DN). In the present study, we investigated whether 12-LO inhibition may ameliorate type-2 DN (T2DN) by interfering with insulin resistance (IR); (2) METHODS: Rat glomerular mesangial cells, glomeruli and skeletal muscles were isolated and used in this study. Kidney histological changes were confirmed by periodic-acid Schiff staining; mRNA expression was detected by competitive reverse transcription polymerase chain reaction; and the protein level was determined by Western blot and the enzyme-linked immunosorbent assay, respectively; (3) RESULTS: The inhibition of 12-LO attenuated microalbuminuria (MAU) increases in type-2 diabetic rats, but not in type-1 diabetic rats. Infusion of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) significantly increased the expression of angiotensin II (Ang II) and Ang II type 1 receptor (AT1R), but decreased the expression of AT1R-associated protein (ATRAP) in rat glomeruli, compared to the control. An in vitro study revealed that both 12(S)-HETE and insulin upregulated AT1R expression in rat mesangial cells. In the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, the 12(S)-HETE-induced ATRAP reduction was significantly abolished. Interestingly, 12-LO inhibition did not influence AT1R expression in type-1 diabetic rats, but significantly abolished the increased AT1R and Ang II expression in glomeruli of type-2 diabetic rats. Furthermore, the inhibition of 12-LO significantly corrected impaired insulin sensitivity and fast serum insulin level, as well as the p-AMP-activated protein kinase (AMPK) reduction in skeletal muscle of type-2 diabetic rats; (4) CONCLUSION: The inhibition of 12-LO potentially ameliorated MAU by preventing IR through the downregulation of glomerular AT1R expression in T2DN.
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. xhz198906@163.com.
authors.forename: Hong-Zhao
authors.initials: HZ
authors.lastname: Xu
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. leoai918@163.com.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. wangwn11@mails.jlu.edu.cn.
authors.forename: Wan-Ning
authors.initials: WN
authors.lastname: Wang
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. docwuhao@sina.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. zhangyuanyuan_1214@163.com.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. renalzangchongsen@163.com.
authors.forename: Chong-Sen
authors.initials: CS
authors.lastname: Zang
authors.affiliation: Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. renalxu@163.com.
authors.forename: Zhong-Gao
authors.initials: ZG
authors.lastname: Xu
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology; D000419:Albuminuria / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D015536:Down-Regulation; D007333:Insulin Resistance; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016859:Lipoxygenase Inhibitors; D047428:Protein Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase
keywords: 12-lipoxygenase; angiotensin II type 1 receptor; diabetic nephropathy; insulin resistance