Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension.
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.


CONCLUSIONS
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.
Klanke
Bernd
B
Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
Cordasic
Nada
N
Hartner
Andrea
A
Schmieder
Roland E
RE
Veelken
Roland
R
Hilgers
Karl F
KF
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D018450:Disease Progression; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology*; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids / Q000009:adverse effects* / Q000494:pharmacology; D009400:Nephrosclerosis / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D013148:Spironolactone / Q000494:pharmacology
D000959:Antihypertensive Agents; D004232:Diuretics; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D006852:Hydrochlorothiazide; D006830:Hydralazine; D013148:Spironolactone; D003900:Desoxycorticosterone; D012110:Reserpine