1. 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.
- Author
-
Xu HZ, Cheng YL, Wang WN, Wu H, Zhang YY, Zang CS, and Xu ZG
- Subjects
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid pharmacology, Albuminuria etiology, Animals, Cells, Cultured, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 metabolism, Down-Regulation, Kidney Glomerulus drug effects, Kidney Glomerulus metabolism, Lipoxygenase Inhibitors pharmacology, Male, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Protein Kinase Inhibitors pharmacology, Rats, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1 genetics, Albuminuria metabolism, Arachidonate 12-Lipoxygenase metabolism, Diabetic Nephropathies metabolism, Insulin Resistance, Receptor, Angiotensin, Type 1 metabolism
- 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.
- Published
- 2016
- Full Text
- View/download PDF