No abstract

Nitric oxide formation is impaired in chronic renal failure. The renoprotective effects of a nonhypotensive dose of HMR1766, a direct activator of the heme enzyme soluble guanylyl cyclase was studied in comparison to an ACE-i in the remnant kidney model. Male Sprague-Dawley rats were subtotally nephrectomized (SNX) or sham operated (sham) and left untreated or started on treatment with HMR1766 or ACE-i in non-hypotensive doses. BP, albumin excretion and parameters of renal damage were analyzed. After a 12-week study, urinary albumin excretion was significantly higher in untreated SNX than in sham; this increase was prevented by ACE-i and ameliorated by HMR1766. Relative kidney and left ventricular weight were significantly higher in untreated SNX compared to sham; these changes were completely prevented by HMR1766. In untreated SNX, glomerulosclerosis (1.02 ± 0.13) was significantly higher than in sham (0.12 ± 0.04), SNX+HMR1766 (0.27 ± 0.04) and SNX+ACE-i (0.46 ± 0.06). Tubulointerstitial changes went in parallel. Increased glomerular cell number after SNX (71.5 ± 14 vs. 60 ± 7.3 in sham) was prevented by HMR1766 (55.7 ± 7.3), but not by ACE-i (66.6 ± 9). The results document beneficial BP-independent HMR1766 effects on kidney structure and urinary albumin excretion in a noninflammatory model of renal failure and may argue for a novel therapeutic principle.

Abstract.A potential role of the sympathetic nervous system in progression of renal failure has received little attention. This study examined whether nonhypotensive doses of moxonidine, an agent that reduces sympathetic activity, affects glomerulosclerosis, urine albumin excretion, and indices of renal handling of norepinephrine (NE) in subtotally nephrectomized (SNX) rats. Sprague Dawley rats were SNX or sham-operated (control). SNX rats were either left untreated or treated with moxonidine in a dose (1.5 mg/kg body wt per d) that did not modify telemetrically monitored 24-h BP. Glomerular and renal morphology were evaluated by quantitative histology, immunohistochemistry, andin situhybridization. Urine albumin excretion rate was analyzed by enzyme-linked immunosorbent assay, and kidney angiotensin II and NE content were measured using HPLC,3H-NE uptake, and release. Body and kidney weight and BP were not significantly different between SNX with or without moxonidine. The glomerulosclerosis index was significantly lower in moxonidine-treated (0.88 ± 0.09) compared with untreated (1.55 ± 0.28) SNX rats, as was the index of vascular damage (0.32 ± 0.14versus0.67 ± 0.16). The number of proliferating cell nuclear antigen-positive glomerular and tubular cells per area was significantly higher in untreated SNX rats than in controls and moxonidine-treated SNX rats. The same was true for urine albumin excretion rate. Renal angiotensin II tissue concentration was not affected by moxonidine. In untreated SNX rats, renal nerve stimulation and exogenous NE induced an increase in isolated kidney perfusion pressure (102 ± 21versus63 ± 8 mmHg). Renal endogenous NE content was significantly lower in SNX rats than in controls (86 ± 14versus140 ± 17 pg/mg wet weight). Cortical uptake of [3H]-NE was not different, but cortical NE release was significantly higher in SNX rats than in controls. Reduced function of presynaptic inhibitory α-adreno-receptors is unlikely because an α2-adrenoceptor antagonist increased NE release. At subantihypertensive doses, moxonidine ameliorates renal structural and functional damage in SNX animals, possibly through central inhibition of efferent sympathetic nerve traffic. In kidneys of SNX rats, indirect evidence was found for increased activity of a reduced number of nerve fibers.

Abstract. Wall thickening of intramyocardial arteries in patients with chronic renal failure may contribute to the increased susceptibility of the uremic heart to ischemic injury. In this context, the following questions arise: (1) Is intramyocardial wall thickening in experimental renal failure due to hypertrophy, hyperplasia or both? (2) Which stimuli trigger wall thickening? Using novel stereologic techniques (Nucleator, Selector), intramyocardial arteries were examined in sham-operated and subtotally nephrectomized (SNX) Sprague Dawley rats with moderate renal failure of 8 wk duration. Systolic BP during the experiment was not significantly different in both groups. Absolute and relative left ventricular weight, wall thickness (5.69 ± 1.11 μm versus 4.42 ± 0.99 μm), and wall-to-lumen ratio of intramyocardial arteries (0.117 ± 0.03 μm/μm versus 0.089 ± 0.01 μm/μm) were significantly greater in SNX than in sham-operated rats. The mean cell and nuclear volume of intramyocardial arteriolar smooth muscle cells was significantly increased in SNX rats (650 ± 230 μm3versus 430 ± 90 μm3 and 26 ± 4.5 versus 19.9 ± 2.2 μm3, respectively). In parallel, the total arteriolar wall volume was significantly greater in the left ventricle of SNX (+ 58%) compared with sham rats. In contrast, the total length of all left ventricular arteries was comparable in both groups. The increase in mean cell volume without significant change in cell number indicates that arteriolar wall thickening in the heart of SNX rats is explained by hypertrophy rather than hyperplasia of arterial smooth muscle cells. This finding in a nonhypertensive experimental model of chronic renal failure contrasts with findings in spontaneously hypertensive rats. Independent of BP and left ventricular hypertrophy, specific growth signals must act on cardiac arteriolar smooth muscle cells.

ABSTRACT. Pharmacologic blockade of the renin and endothelin (ET) systems is an established strategy to interfere with progression of renal failure. In the Heyman nephritis model, additive benefits of decreases in BP with the combination of angiotensin-converting enzyme inhibitors (ACE-i) and ETAreceptor antagonists (ET-RA) were demonstrated. To further investigate these findings and to exclude confounding effects of BP decreases, this issue was reassessed in a low-renin model of subtotal kidney resection. Subtotally nephrectomized (SNX) and sham-operated rats were left untreated or received an ACE-i, an angiotensin II subtype 1 receptor antagonist (AT1-RA), an ET-RA, or combinations thereof (ACE-i plus ET-RA or AT1-RA plus ET-RA). The parameters studied were the glomerulosclerosis index (GSI), tubulointerstitial index, vascular damage index, glomerular geometry, and albumin excretion. After 12 wk, BP values were comparable. Urinary albumin excretion rates were significantly higher for untreated SNX rats (24.3 ± 31.3 mg/24 h), compared with untreated sham-operated rats (0.71 ± 0.40 mg/24 h). Rates were significantly lower for all treated, compared with untreated, SNX groups. GSI values were significantly higher for untreated SNX rats than for untreated sham-operated rats. ACE-i caused significantly lower GSI in SNX rats (0.46 ± 0.06), compared with AT1-RA (0.60 ± 0.10) or ET-RA (0.65 ± 0.10). GSI values were significantly decreased further with ACE-i plus ET-RA (0.29 ± 0.09) or AT1-RA plus ET-RA (23 ± 0.05) treatment. Changes in the tubulointerstitial index and vascular damage index proceeded in parallel. The results document BP-independent effects of the ACE-i and AT1-RA on the GSI and urinary albumin excretion and an effect of the ET-RA on the GSI. The contrasting results suggest different pathogenetic pathways for glomerulosclerosis and albuminuria. The combination of treatments provided superior effects on the GSI and tubulointerstitial index but not on urinary albumin excretion.