Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model

Abstract

Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.

Keywords: calcium channel blockers; hypertension; renal circulation; renin-angiotensin system.

Figure 1. Course of radiotelemetrically measured systolic BP

Weekly averages of radiotelemetrically recorded systolic BP (mean ± SEM) at baseline (week 0) and over the subsequent 4 weeks in the 4 groups of SHRsp which received as drinking fluid (i) 1% NaCl (ii) 1% NaCl + enalapril (iii) 1% NaCl + a combination of hydralazine and hydrochlorothiazide (H/H) and (iv) 1% NaCl + amlodipine. The baseline BP was the average systolic BP during the last 3 days before the initiation of a Japanese style diet and salt-supplementation. Six of 27 untreated rats were euthanized for humane reasons between the 3^rd and 4^th week (see Methods for details). * p<0.05 maximum vs. the untreated 1% NaCl only group, δ p<0.05 maximum vs 1% NaCl + enalapril group.

Figure 2. Correlation between systolic BP and renal damage

Linear regression analysis of the correlation of histologic composite renal damage score in individual SHRsp with their respective average systolic BP during the final 2 weeks before study termination (n=70). For individual rats with average final 2 week systolic BP <190mmHg (n=41), slope = 0.17±0.04, r² = 0.33, p<0.0001; for rats with average final 2 week systolic BP >190mmHg (n=29), slope = 1.2±0.2, r² = 0.6, p<0.0001.

Figure 3

Group BP data for all the SHRsp rats (n=27) that underwent Protocol B studies. Systolic BP (mmHg) and proteinuria (mg/24 hrs) are shown for baseline, the final 2 weeks before right uninephrectomy and initiation of antihypertensive therapy (AHT) and for 2 (n=14) or 3 weeks (n=13) after initiation of AHT. *p<0.001 vs. baseline; δ p<0.01 maximum vs. all other groups.

Figure 4

Representative photomicrographs of right kidneys removed from rats on Japanese style diet and 1% salt drinking water prior to antihypertensive treatment (RK) and left kidneys remaining in rats on the same regimen following Hydralazine and Hydrochlorothiazide treatment (LK). Top panels (Masson Trichrome) show arteriolosclerosis (arrowhead), glomerular necrosis (arrow), interstitial infiltrates and fibrosis in RK but not in LK. Middle and bottom panels (hematoxylin and eosin) show arteriolar necrosis and glomerular necrosis in RK (middle panel), proliferative occlusive arteriolosclerosis with RBC in arteriolar wall in RK (bottom panel), and arterioles with nearly normal morphology in LK (middle and bottom panels). Arrowheads – arterioles. Asterisks – interlobular artery. V—Vein. Micron Bar: 100µm

Figure 5

Quantitation and distribution of hypertensive vascular and glomerular injury lesions for the right kidney before antihypertensive therapy and the perfused-fixed left kidney harvested at termination of studies after 2–3 weeks of antihypertensive therapy with the H&H regimen. * p<0.02 vs. pre AHT; maximum