Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats.
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, and in situ hybridization. Urine albumin excretion rate was analyzed by enzyme-linked immunosorbent assay, and kidney angiotensin II and NE content were measured using HPLC, (3)H-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 +/- 0.14 versus 0.67 +/- 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 +/- 21 versus 63 +/- 8 mmHg). Renal endogenous NE content was significantly lower in SNX rats than in controls (86 +/- 14 versus 140 +/- 17 pg/mg wet weight). Cortical uptake of [(3)H]-NE was not different, but cortical NE release was significantly higher in SNX rats than in controls. Reduced function of presynaptic inhibitory alpha-adreno-receptors is unlikely because an alpha(2)-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.
Amann
Kerstin
K
Department of Pathology, University of Heidelberg, Germany.|Department of Pathology, University of Erlangen-Nürnberg, Germany.
Rump
Lars Christian
LC
Department of Internal Medicine IV, University of Freiburg, Germany.
Simonaviciene
Aurelia
A
Department of Pathology, University of Heidelberg, Germany.
Oberhauser
Vitus
V
Department of Internal Medicine IV, University of Freiburg, Germany.
Wessels
Sabine
S
Department of Pathology, University of Heidelberg, Germany.
Orth
Stephan R
SR
Department of Internal Medicine, University of Heidelberg, Germany.
Gross
Marie-Luise
ML
Department of Pathology, University of Heidelberg, Germany.
Koch
Andreas
A
Department of Pathology, University of Heidelberg, Germany.
Bielenberg
Gerhard W
GW
Solvay Pharma, Hannover, Germany.
VAN Kats
Jorge P
JP
Department of Internal Medicine, Erasmus University, Rotterdam, The Netherlands.
Ehmke
Heimo
H
Department of Physiology, University of Hamburg, Germany.
Mall
Gerhard
G
Department of Pathology, Darmstadt, Germany.
Ritz
Eberhard
E
Department of Internal Medicine, University of Heidelberg, Germany.
D000419:Albuminuria / Q000503:physiopathology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000294:innervation; D008297:Male; D009392:Nephrectomy / Q000379:methods*; D009433:Neural Inhibition; D009638:Norepinephrine / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics
D000959:Antihypertensive Agents; D007093:Imidazoles; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C043482:moxonidine; D009638:Norepinephrine