Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats

Abstract

receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats. Am J Physiol Renal Physiol 297: F802-F808, 2009. First published June 17, 2009 doi:10.1152/ajprenal.00197.2009.-We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n ϭ 12), eplerenone (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , po, n ϭ 12), amlodipine (3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , po, n ϭ 12), or eplerenone plus amlodipine (n ϭ 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects. interstitial fibrosis; hypoxia; salt-sensitive hypertension HYPERTENSION IS THE PRIMARY risk factor for the progression of renal disease and one of the major causes of chronic kidney disease (1, 9). Although there are effective drugs available for hypertension, preventing the development and progression of concomitant diminished renal function remains paramount.Eplerenone, a selective mineralocorticoid receptor (MR) antagonist, has been used as an antihypertensive drug. We and others have demonstrated that aldosterone induces cell proliferation and deformability in rat mesangial cells (21) and increases oxidative stress in murine podocytes (24); these changes were suppressed by eplerenone. Interestingly, eplerenone suppressed the development of glomerular injury in salt-fed Dahl salt-sensitive (DS) rats despite low plasma aldosterone levels (17). Moreover, clinical studies reported that treatment with eplerenone reduced albuminuria to a greater extent than treatment with an angiotensinconverting enzyme inhibitor, enalapril, with a similar degree of hypotensive ...

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

“…37 In a recent paper, amlodipine improved oxygen conditions, restored the loss of peritubular capillaries and prevented tubulointerstitial fibrosis in the kidney of DS rats with high salt loading for 10 weeks. 38 However, we did not observe any tubulointerstitial fibrosis in the kidneys of high salt-loaded DS rats at 4 weeks. The usefulness of combination therapy with irbesartan and amlodipine for protection of tubules and the interstitium should be evaluated in further studies.…”

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

“…5 Crosstalk and interactions between the MR and the angiotensin receptor 1 have also been proposed to contribute to end-organ damage in both the heart and kidneys. 45 Although the data from expression studies and investigations into the effects of aldosterone infusions have provided valuable insights into MR signaling, perhaps the most compelling evidence for the pathophysiological role of MR activation has come from the demonstration of the protective effects of the currently available MRAs, spironolactone, and eplerenone, in models of cardiac and renal diseases ( Figure; also Table S1 in the online-only Data Supplement). Treatment with an MRA attenuates or prevents cardiac hypertrophy and the development of HF in several experimental models of heart disease (Table S1).…”

Treatment of Hypertension and Renal Injury Induced by the Angiogenesis Inhibitor Sunitinib

“…9 In the third experiment, rats were administered the combination of sunitinib and amlodipine 3 mg/kg per day by oral gavage for 8 days. 10,11 In the fourth experiment, rats (n=9) were administered the combination of sunitinib by oral gavage and captopril at 3 or 12 mg/kg per day (C4042, Sigma-Aldrich) using osmotic minipumps (Alzet 2ml2) for 8 days. 12,13 In the final experiment, rats (n=6) were administered the combination of sunitinib and sildenafil 1.5 mg/kg per day (Revatio; Pfizer).…”