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

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. and Forbes, J. M. (2010) 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. Diabetologia, 53 11: 2442-2451. doi:10.1007/s00125-010-1837-2


Author 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.
Title 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
Journal name Diabetologia   Check publisher's open access policy
ISSN 0012-186X
1432-0428
Publication date 2010-11
Sub-type Article (original research)
DOI 10.1007/s00125-010-1837-2
Open Access Status Not Open Access
Volume 53
Issue 11
Start page 2442
End page 2451
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
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.
Keyword Advanced glycation
Angiotensin
AT1 receptor
AT2 receptor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
UQ Centre for Clinical Research Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 25 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 34 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 05 Jan 2015, 11:41:24 EST by Ms Kate Rowe on behalf of Scholarly Communication and Digitisation Service