Effects of Low Dose Sympathetic Inhibition on Glomerulosclerosis and Albuminuria in Subtotally Nephrectomized Rats

Abstract

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.

Chromogranin A pathway: from pathogenic molecule to renal disease

“…In obese spontaneously hypertensive rats, progressive increase in blood pressure, cardiac remodeling and renal injury were mediated by renal sympathetic activation as they were attenuated by renal sympathetic denervation [35]. In 5/6th nephrectomized rats sympathectomy attenuated hypertension; however, the level of proteinuria in these rats was reduced to a greater extent than what would be expected solely on the basis of lower blood pressure confirming involvement of sympathetic nervous system [36]. Campese's study [37] indicates that increased sympathetic nervous system activity contributes to the pathogenesis of hypertension and progressive glomerulosclerosis in rats with the renal ablation model of chronic renal failure.…”

Moderate hyperuricaemia ameliorated kidney damage in a low‐renin model of experimental renal insufficiency

“…The reliability of the histological ndings is supported by the good correlation between the glomerulosclerosis score and the amount of 24-hour urinary protein excretion. The hypertrophy of the remnant kidney can be attributed to compensatory tissue growth in an attempt to compensate for the reduced renal function (31,32). The NX rats presented with low plasma renin activity probably due to the associated volume load, corresponding to previous ndings in rats subjected to surgical renal ablation (20).…”

“…Notably, the therapeutic effects of XO inhibitors have not been solely related to reduced UA concentrations but also to the anti‐oxidative and anti‐inflammatory properties of these compounds 37 . The 5/6 NX model has also been characterized by reduced tissue XO activity and a compensatory increase in intestinal UA excretion 38 . These mechanisms may explain why plasma UA was not significantly higher in the NX rats on the normal diet than in Sham rats on the normal diet.…”

“…The reliability of the histological findings is supported by the good correlation between the glomerulosclerosis score and 24‐h urinary protein excretion. Surgical subtotal NX results in marked glomerular hypertrophy so that the size of the glomeruli is increased almost three times when compared with sham‐operated controls 38 . The hypertrophy of the remnant kidney can be attributed to compensatory tissue growth in an attempt to compensate for the reduced renal function 38,40 .…”

Place of imidazoline receptor agonists in the treatment of hypertension

“…Динамику уровней этих маркеров авторы исследования объясняли нормализацией состояния эндотелия на фоне лечения [21]. Моксонидин в малых дозах может замедлить развитие гломерулосклероза [22]. Нефропротективный эффект моксонидина отмечен, в т.ч.…”