NDT Advance Access originally published online on May 30, 2008
Nephrology Dialysis Transplantation 2008 23(11):3456-3463; doi:10.1093/ndt/gfn301
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension*
1 Department of Nephrology and Hypertension 2 Children and Youth Hospital, University of Erlangen-Nuremberg, Erlangen, Germany
Correspondence and offprint requests to: Karl F. Hilgers, Nephrology Research Laboratory, Loschgestrasse 8, D-91054 Erlangen, Germany. Tel: +49-9131-8536314; Fax: +49-9131-8535821; E-mail: karl.hilgers{at}uk-erlangen.de
 |
Abstract |
|---|
Objective. We examined the contribution of high blood pressure versus direct mineralocorticoid effects to the progression of kidney inflammation and fibrosis in established experimental deoxycorticosterone-acetate (DOCA)-salt hypertension.
Methods. Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. After 4 weeks of DOCA-salt hypertension, rats were either killed (n = 6), or treated with a non-hypotensive dose of spironolactone (n = 7) or triple therapy (hydrochlorothiazide, reserpine and hydralazine, n = 8) to normalize blood pressure or with vehicle (n = 19) for two further weeks. Mean arterial pressure (MAP) was measured intra-arterially. Glomerulosclerosis, interstitial fibrosis, macrophage infiltration and complement deposition were evaluated on kidney sections. Expression of collagens, chemokines and cytokines was measured by real-time PCR.
Results. MAP was elevated in DOCA rats, not affected by spironolactone and normalized by triple therapy. Glomerulosclerosis and interstitial fibrosis of DOCA rats were alleviated by spironolactone and triple therapy. Macrophage infiltration, complement C3 deposition and nitrotyrosine staining in the kidney were significantly reduced by spironolactone as well as triple therapy. The expression of collagens, chemokines, adhesion molecules and profibrotic cytokines in the kidney was elevated in hypertension and decreased by triple therapy but not significantly affected by spironolactone.
Conclusion. Direct mineralocorticoid effects as well as high blood pressure per se contribute to inflammation and fibrosis of the kidney. Oxidative stress may mediate the direct mineralocorticoid effects on kidney inflammation.
Keywords: aldosterone; glomerulosclerosis; kidney; macrophages; nephrosclerosis
* Presented at the 60th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research of the American Heart Association, 2005.
Received for publication: 3.10.07
Accepted in revised form: 5. 5.08