Clinical and animal studies have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists slows the progression of nephropathy in diabetes, indicating that Ang II plays an important role in its development. We have reported previously that insulin inhibits the stimulatory effect of high glucose levels on angiotensinogen (ANG) gene expression in rat immortalized renal proximal tubular cells (IRPTCs) via the mitogen-activated protein kinase (p44/42 MAPK) signal transduction pathway. We hypothesize that the suppressive action of insulin on ANG gene expression might be attenuated in renal proximal tubular cells (RPTCs) of rats with established diabetes. Two groups of male adult Wistar rats were studied: controls and streptozotocin (STZ)-induced diabetic rats at 2, 4, 8 and 12 weeks post-STZ administration. Kidney proximal tubules were isolated and cultured in either normal glucose (i.e. 5 mM) or high glucose (i.e. 25 mM) medium to determine the inhibitory effect of insulin on ANG gene expression. Immunoreactive rat ANG (IR-rANG) in culture media and cellular ANG mRNA were measured by a specific radioimmunoassay and reverse transcription-polymerase chain reaction assay respectively. Activation of the p44/42 MAPK signal transduction pathway in rat RPTCs was evaluated by p44/42 MAPK phosphorylation employing a PhosphoPlus p44/42 MAPK antibody kit. Insulin (10(-7) M) inhibited the stimulatory effect of high glucose levels on IR-rANG secretion and ANG gene expression and increased p44/42 MAPK phosphorylation in normal rat RPTCs. In contrast, it failed to affect these parameters in diabetic rat RPTCs. In conclusion, our studies demonstrate that hyperglycaemia induces insulin resistance on ANG gene expression in diabetic rat RPTCs by altering the MAPK signal transduction pathway.

This article has been cited by other articles:

				C.-C. Wei, S.-L. Zhang, Y.-W. Chen, D.-F. Guo, J. R. Ingelfinger, K. Bomsztyk, and J. S. D. Chan Heterogeneous Nuclear Ribonucleoprotein K Modulates Angiotensinogen Gene Expression in Kidney Cells J. Biol. Chem., September 1, 2006; 281(35): 25344 - 25355. [Abstract] [Full Text] [PDF]

				T.-J. Hsieh, P. Fustier, C.-C. Wei, S.-L. Zhang, J. G Filep, S.-S. Tang, J. R Ingelfinger, I G. Fantus, P. Hamet, and J. S D Chan Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells J. Endocrinol., December 1, 2004; 183(3): 535 - 550. [Abstract] [Full Text] [PDF]

				T.-J. Hsieh, P. Fustier, S.-L. Zhang, J. G. Filep, S.-S. Tang, J. R. Ingelfinger, I. G. Fantus, P. Hamet, and J. S. D. Chan High Glucose Stimulates Angiotensinogen Gene Expression and Cell Hypertrophy via Activation of the Hexosamine Biosynthesis Pathway in Rat Kidney Proximal Tubular Cells Endocrinology, October 1, 2003; 144(10): 4338 - 4349. [Abstract] [Full Text] [PDF]

				S.-L. Zhang, X. Chen, C.-C. Wei, J. G. Filep, S.-S. Tang, J. R. Ingelfinger, and J. S. D. Chan Insulin Inhibits Dexamethasone Effect on Angiotensinogen Gene Expression and Induction of Hypertrophy in Rat Kidney Proximal Tubular Cells in High Glucose Endocrinology, December 1, 2002; 143(12): 4627 - 4635. [Abstract] [Full Text] [PDF]