Ageing, hypertension and the kidney: new data on an old problem

Xiaoyan Zhou and Edward D. Frohlich

Hypertension Research Laboratories, Ochsner Clinic Foundation, New Orleans, LA, USA

Correspondence and offprint requests to: Edward D. Frohlich, MD, Alton Ochsner Distinguished Scientist, Ochsner Clinic Foundation, 1516 Jefferson Highway, New Orleans, LA 70121, USA. Email: efrohlich{at}ochsner.org

Keywords: co-morbidity; diabetes mellitus; endothelial system; end-stage renal disease; renin–angiotensin–aldosterone system; spontaneously hypertensive rats

Introduction

End-stage renal disease (ESRD) has become an increasingly common health problem, even for the elderly, especially in the developed countries [13]. From 1997 to 2000, the incidence rate of ESRD among patients aged 65 to 74 and those >= 75 years old has increased to 7.8% and 22.3%, respectively, in the United States [1]. The leading causes of ESRD are diabetes mellitus and hypertension, and hypertension is a very frequent co-morbid condition of diabetes. Both are exceedingly common in the elderly, and they dramatically exacerbate ESRD development [4]. Of particular interest is that experimental studies in recent years have shown similar renal haemodynamic, glomerular dynamic, renal functional and histopathological changes in both diabetic nephropathy and hypertensive renal injuries [58]. These pathophysiological alterations are characterized by diminished renal blood flow and increased renal vascular resistance, markedly increased afferent and efferent glomerular arteriolar resistances, and associated with elevated glomerular hydrostatic pressure, hyperfiltration, proteinuria, and nephrosclerosis [8,9]. The principal mechanisms underlying the foregoing pathophysiological changes have been shown to involve (among many other factors) the local renal renin–angiotensin–aldosterone system [10] and endothelial system [11], which have been confirmed by the mounting evidence that inhibition of these factors produces renoprotective effects [5,6,1214]. This review focuses on our studies involving ESRD in spontaneously hypertensive rats (SHR) and the effects of pharmacological intervention in this model.

Ageing, hypertension and the kidney

Over the past decade we have been involved with renal micropuncture studies of naturally developing SHR, a model highly analogous to essential hypertension in man [15]. At 20 weeks of age this model has increased total renal vascular and glomerular afferent arteriolar resistances without impaired renal flow and function [1618]. At 73 weeks, however, we have demonstrated natural progression of SHR nephrosclerosis to ESRD, manifested by increased arterial pressure, reduced total renal blood flow and increased renal vascular resistance, markedly increased afferent and efferent glomerular arteriolar resistances and glomerular hydrostatic pressure, and segmental or global glomerular and arteriolar sclerosis associated with inflammatory cell infiltration, interstitial fibrosis, atrophic and dilated tubules, and tubular casts [6]. These findings strongly suggest that the severity of renal damage was dependent upon the intensity and duration of hypertension and was exacerbated by ageing [8]. Of great clinical relevance and importance are the findings that patients with essential hypertension who have developed ESRD demonstrate similar alterations to those of these aged SHR with naturally developing ESRD [12,19,20]. Therefore, aged SHR can be plausibly considered as an ideal experimental model for naturally developing ESRD. However, because of the exceedingly high cost of maintaining younger SHR until 73 weeks [8,12], it was necessary to modify this experimental model in order to mimic those changes observed in the aged SHR with naturally occurring ESRD.

L-NAME/SHR model of ESRD in the aged SHR

A number of studies have demonstrated that nitric oxide (NO), the endogenous endothelial vasodilator synthesized by the constitutive enzyme NO synthase, plays a critical role in the natural regulation of renal haemodynamics and excretory function [8,2123]. Chronic NO synthase blockade was shown to activate the renin–angiotensin and sympathetic nervous systems, increase systemic and renal vascular tone and reduce renal blood flow and glomerular filtration rate [22,23]. Based upon this crucial evidence, we developed a protocol to test the hypothesis that prolonged administration of the NO synthase enzymatic inhibitor N{omega}-nitro-L-arginine methyl ester (L-NAME) to younger adult SHR will reproduce the pathophysiological alterations associated with naturally occurring nephrosclerosis in the 73-week-old aged SHR. In that study, we inhibited synthesis of endothelial-derived NO in 17-week-old young SHR by administering L-NAME in drinking water (50 mg/l) for 3 weeks. Our results demonstrated that the massive proteinuria induced by L-NAME was associated with intense afferent and efferent glomerular arteriolar constriction and, pathologically, with hypertensive nephrosclerosis that was manifested by severe afferent arteriolar fibrinoid necrosis, segmental glomerular hyalinosis and sclerosis, and renal ischaemia [8,24]. These findings were remarkably similar to those alterations we had observed earlier in the naturally developing severe nephrosclerosis of the 73-week-old SHR. Therefore, the L-NAME/SHR model of ESRD in the aged SHR became an important adjunct to our studies of the pathogenesis of ESRD in the SHR and our inquiries into the effects of various pharmacological interventions on the development, progression, and even reversal of ESRD.

Differential effects of pharmacological interventions

Since developing the L-NAME/SHR model of ESRD, we have performed a series of studies directed towards exploration of the question of whether pharmacological therapy could prevent or reverse L-NAME/SHR-exacerbated nephrosclerosis. In those studies we examined the renal effects of the more commonly used antihypertensive agents in this model by haemodynamic and micropuncture techniques as well as by morphological analysis.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor antagonists
We had previously reported that treatment with the ACE inhibitor quinapril for no more than 3 weeks dramatically improved all the pathophysiological indices in the naturally occurring hypertensive nephrosclerosis of 73-week-old SHR [6]. We subsequently administered ACE inhibitors (e.g. quinapril, enalapril) [2527] or AT1 receptor antagonist (e.g. candesartan) [27] simultaneously with L-NAME for 3 weeks in younger 17-week-old SHR, and found that the development of hypertensive nephrosclerosis was indeed prevented. Furthermore, when the ACE inhibitors or AT1 receptor antagonist was administered for a subsequent 3-week period after the 3-week period of L-NAME, the severe L-NAME-induced pathophysiological changes of nephrosclerosis were significantly reversed or normalized. It should be noted that the L-NAME-induced nephrosclerosis in SHR could not be reversed during a 3-week period following L-NAME withdrawal. Thus, not only did ACE inhibition and AT1 receptor antagonism significantly ameliorate the development and progression of ESRD, but they also reversed the established pathophysiological alterations. These responses to ACE inhibition or AT1 receptor antagonism observed in L-NAME-exacerbated nephrosclerosis in younger adult SHR were remarkably similar to the reversal of changes achieved in very old SHR as well as in hypertensive patients with ESRD. These studies also showed that AT1 receptor antagonism and ACE inhibition produced similar renoprotective effects, and provided strong evidence of beneficial renal effects afforded by these agents in either the elderly SHR or in L-NAME/SHR. Moreover, the data also suggested that inhibition of the renal effects of the renin–angiotensin system was the principal mechanism underlying the renoprotective actions of these agents that inhibit the renin–angiotensin system. Additionally, we demonstrated that inhibition of bradykinin degradation by ACE provided no additional renoprotection as suggested by studies in which a bradykinin receptor antagonist was co-administered with the ACE inhibitor.

Calcium antagonists
The effects of various calcium antagonists on the development and progression of hypertensive renal injury were also studied extensively in experimental models as well as in hypertensive patients; however, the data were conflicting [13]. These contradictory findings were most frequently attributed to structural and pharmacological differences between these agents, the modes of dosing, and the experimental models employed. We therefore investigated the effects of various calcium antagonists (e.g. felodipine, amlodipine, mibefradil and cilnidipine) [26,28,29] on systemic and renal haemodynamics, glomerular dynamics and pathological changes in the L-NAME/SHR model of nephrosclerosis. In these studies, each of these four calcium antagonists, regardless whether the L-, T-, or N-calcium-channel receptors were inhibited, prevented and reversed the intrarenal glomerular and arteriolar histological lesions and physiological changes. Although there were some minor differences in responses between the four calcium antagonists, they did not differ substantially with respect to their renal and intrarenal effects. Moreover, these remarkable improvements were comparable to those produced by ACE inhibition or AT1 receptor antagonism. Furthermore, the combination therapy of the ACE inhibitor enalapril and the calcium antagonist felodipine (used in half-dosage of each agent to reduce mean arterial pressure to the same extent as full doses of either agent) did not produce a greater renoprotective effect than did monotherapy with either of the two agents alone. It is important to mention that most conventional calcium antagonists have been reported to dilate glomerular afferent arterioles preferentially [13]. However, we demonstrated that three types of calcium-channel receptor antagonists in the L-NAME/SHR dilated both afferent and efferent arterioles, and thereby reduced glomerular hydrostatic pressure and exerted beneficial renal histological effects.

Diuretics
Diuretics were among the first drugs employed to treat hypertension, and have been remarkably effective particularly in elderly, obese, and black patients. However, few experimental or clinical studies have been performed or demonstrated their effects on the progression of hypertensive renal disease [13]. We therefore evaluated the responses of this class of antihypertensive agents in the L-NAME/SHR model of ESRD using hydrochlorothiazide (HCTZ) [30]. HCTZ was co-administered with the L-NAME for 3 weeks, and systemic arterial pressure was reduced to a level similar to that achieved with ACE inhibitors or calcium antagonists in our other studies. However, HCTZ increased glomerular hydrostatic pressure associated with glomerular efferent arteriolar constriction and unchanged afferent arteriolar resistance, exacerbation of glomerular and arteriolar injuries and proteinuria. Thus, these findings demonstrated diuretic-induced changes in L-NAME/SHR actually further impaired glomerular dynamics and enhanced histological alterations. These adverse effects were most probably the result of stimulation of both the systemic and the local intrarenal renin–angiotensin systems.

Conclusion

Our experimental studies have demonstrated that most antihypertensive agents, including ACE inhibitors and AT1 receptor antagonists [2527], calcium antagonists [26,28,29], but not diuretics [30], prevented and reversed L-NAME-induced exacerbation of hypertensive nephrosclerosis in SHR. Moreover, we emphasize that the suboptimal reduction of arterial pressure in itself was most probably insufficient to prevent or reverse hypertensive ESRD. The beneficial effects can probably be attributed to the direct renal actions of these drugs. These experimental findings provided us with clear-cut evidence that these agents not only reversed, but also prevented ESRD in this experimental model and in essential hypertension. The increasing incidence and prevalence of ESRD, particularly in the elderly population, underscores the necessity of pharmacological intervention to prevent and reverse ESRD. Although numerous clinical studies have shown that ACE inhibitors and AT1 receptor antagonists have been effective in slowing the rate of progression and improving survival in ESRD, additional long-term, prospective clinical trials with various calcium antagonists and diuretics are expected to be performed.

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