Role of Aldosterone in Renal Vascular Injury in Stroke-Prone Hypertensive Rats

Abstract

Abstract-Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (nϭ8); captopril alone (50 mg ⅐ kg; or captopril and aldosterone at 20 (nϭ6) or. Systolic blood pressure was markedly elevated in all groups. Vehicle-and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21Ϯ3% and 29Ϯ3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 g ⅐ kg Ϫ1 ⅐ d Ϫ1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16Ϯ3% and 21Ϯ2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure. Key Words: hypertension Ⅲ kidney Ⅲ malignant nephrosclerosis Ⅲ captopril Ⅲ aldosterone T he participation of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertensive vascular injury has been widely demonstrated. 1 Numerous studies with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin (Ang) II receptor antagonists have clearly identified Ang II as a major factor responsible for the development of end-organ damage in hypertensive vascular disease. However, mineralocorticoids may also play an important role, because animals with deoxycorticosterone acetate (DOCA)-salt hypertension typically develop severe vascular pathology, and resultant malignant nephrosclerosis, myocardial necrosis, and stroke, 2-5 despite low levels of plasma renin activity. 2,5,6 The renal lesions that develop in DOCA-salt hypertensive rats are characterized by fibrinoid necrosis of blood vessels and proliferative arteriopathy 2-4 and are very similar to those seen in stroke-prone spontaneously hypertensive rats (SHRSP) receiving a high sodium chloride diet 7-11 and in rats with Ang II-salt-induced hypertension. 12 We have shown that chronic administration of agents that inter...

Effects of Aldosterone on the Vasculature

“…11,[35][36][37] This may occur more frequently in the presence of high salt, which sensitizes the cardiovascular system to the nefarious cardiovascular inflammatory effects of aldosterone. Inflammatory responses have increasingly been associated with mechanisms involved in the pathophysiology of cardiovascular disease.…”

Aldosterone as a Mediator of Progressive Renal Dysfunction: Evolving Perspectives.

“…Data from this analysis are shown in Fig. 2 (12). Animals in the control and aldosterone infusion groups experienced marked proteinuria and comparable degrees of renal injury (21 %and 29%, respectively).…”

“…Although many studies have demonstrated a beneficial ef-feet of ACEinhibition in retarding progressive renal disease, it must be emphasized that this intervention does not differentiate between the relative contribution of renin-angiotensin versus aldosterone. To evaluate the possible contribution of aldosterone per se, Rocha et al conducted a series of experiments in SHRSPthat succeeded in dissociating the relative contributions of aldosterone and the renin-angiotensin system (12,32). Initially, they implanted time-release pellets of spironolactone, an aldosterone receptor antagonist, or placebo pellets in saline-drinking (1% NaCl) SHRSP ingesting a Stroke-Prone Rodent diet (32).…”

“…In a subsequent study, Rocha et al (12) investigated whether an aldosterone infusion wouldreverse the renal-protective effects of captopril therapy in SHRSP. The study divided SHRSP into five groups: vehicle (control), captopril (50 mg/kg/day), aldosterone infusion (40 jig/kg/day), or captopril (50 mg/kg/ day) with aldosterone infusion (at 20 and 40 |Lig/kg/day).…”

“…As described previously, Rocha et al (32) demonstrated that aldosterone receptor blockade with spironolactone markedlyattenuated urinary protein excretion, as well as prevented the development of nephrosclerotic and cerebrovascular lesions, independent of changes in arterial blood pressure in saline-drinking SHRSRSpironolactone, although an effective aldosterone receptor antagonist, also has affinity for other steroid receptors, thereby producing unwanted adverse effects. Consequently, the same investigators recently conducted a second study using eplerenone, a selective aldosterone receptor antagonist (58). Using the same saline-drinking SHRSP model, investigators performed two experiments to evaluate whether eplerenone wouldprovide the samerenal-protective effects as spironolactone.…”