Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor

• Published in: Diabetologia 2010-11, Vol.53 (11), p.2442-2451
• Main Authors: Sourris, K. C, Morley, A. L, Koitka, A, Samuel, P, Coughlan, M. T, Penfold, S. A, Thomas, M. C, Bierhaus, A, Nawroth, P. P, Yamamoto, H, Allen, T. J, Walther, T, Hussain, T, Cooper, M. E, Forbes, J. M
• Format: Article
• Language: English
• Subjects: Advanced glycation; Angiotensin; Animals; Associated diseases and complications; AT1 receptor; AT2 receptor; Biological and medical sciences; Chronic kidney disease; Diabetes; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - therapy; Diabetic nephropathy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Human Physiology; Humans; Internal Medicine; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Function Tests; Kidneys; Male; Medical research; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Knockout; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Proteins; Random Allocation; Rats; Receptor for Advanced Glycation End Products; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Renal failure; Superoxides - metabolism; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1837-2

Aims/hypothesis The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. Methods Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor (At2 knockout [KO]) or RAGE (Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. Results With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. Conclusions/interpretation RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy.