Regression of Glomerular and Tubulointerstitial Injuries by Dietary Salt Reduction with Combination Therapy of Angiotensin II Receptor Blocker and Calcium Channel Blocker in Dahl Salt-Sensitive Rats

Abstract

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

“…Significant hypertrophy occurs in several models of hypertension including the ANG II, 5/6 nephrectomy, and salt-sensitive hypertension models (3,23,17,30). Indeed, the concentration of ANG II in Bowman's space has been shown to be 1,000-fold higher than in the systemic circulation (36).…”

“…In this study, we show that ANG II-induced glomerular hypertrophy was independent of blood pressure or hormonal status, suggesting a local role for ANG II in modifying renal architecture, separate from changes in blood pressure. Indeed, angiotensin receptor blocker administration in male Ren-2 transgenic rats can partially prevent glomerular volume expansion in the 5/6 nephrectomy model of hypertension (17), while the combination therapy of a calcium channel blocker (azelnidipine) and an angiotensin receptor blocker (olmesartan) given to male saltsensitive rats reduces mean glomerular area to a greater degree than when either is given alone (30). Interestingly, blood pressures in the treatment groups were also reduced, making it difficult to determine whether the reduction in glomerular area was a result of blood pressure normalization or a function of angiotensin receptor antagonism.…”

“…We included an estrogen replacement group in the menopause study. We examined renal damage, including glomerular hypertrophy, to determine the role of sex hormones in this disease process (17,30).…”

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

“…injury that was reversed by switching to a normal salt diet (Rafiq et al, 2014). In another report, it has been shown that, in an adenine-loaded rat, which is widely used as a model for renal failure, cessation of the adenine diet led to the reversal of renal damage (Shuvy et al, 2011).…”

“…Recently, Rafiq et al (2014) demonstrated that high-salt loading to Dahl salt-sensitive hypertensive rats induced renal Fig. 6.…”