Aldosterone antagonism ameliorates proteinuria and nephrosclerosis independent of glomerular dynamics in L-NAME/SHR model.
BACKGROUND
The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition.


METHODS
Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 +/- 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 +/- 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9).


RESULTS
L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 +/- 26.5 vs. 51.9 +/- 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 +/- 9 vs. 29 +/- 9 score/100 glomeruli, p < 0.01; 116 +/- 18 vs. 41 +/- 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 +/- 0.07 vs. 0.39 +/- 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone.


CONCLUSIONS
The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.
Zhou
Xiaoyan
X
Hypertension Research Laboratories, Ochsner Clinic Foundation, New Orleans, LA, USA.
Ono
Hidehiko
H
Ono
Yuko
Y
Frohlich
Edward D
ED
D000818:Animals; D000077545:Eplerenone; D006439:Hemodynamics / Q000187:drug effects; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009400:Nephrosclerosis / Q000188:drug therapy* / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D011918:Rats, Inbred SHR; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone; D019331:NG-Nitroarginine Methyl Ester