Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers.
BACKGROUND
Uremia is characterized by inadequately increased sympathetic activity. Sympathetic overactivity is involved in the genesis of hypertension in uremia, but its potential role on progression has not been well investigated. To address this issue, the effect of subantihypertensive doses of an alpha blocker and a beta blocker, and their combination on renal morphology and on albuminuria were investigated in the model of the subtotally nephrectomized rat.


METHODS
Male Sprague-Dawley rats were subjected to surgical ablation (SNX) or sham operation (sham). Three days after surgery groups were treated either with phenoxybenzamine (PBZ, 5 mg/kg body weight/day), metoprolol (MET, 150 mg/kg body weight/day) or their combination (PBZ 2.5 mg/kg body weight/day + MET, 50 mg/kg body weight/day). Renal morphology was evaluated after 12 weeks by quantitative histology, immunohistochemistry, and electron microscopy. Urine albumin excretion and kidney endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) mRNA expression were assessed.


RESULTS
Systolic blood pressure was significantly higher in all SNX groups compared with sham-operated controls with no difference in the SNX groups. The number of glomeruli per left kidney was reduced from 30,904 +/- 3212 to 17,480 +/- 2341 by SNX (-43.5%). Mean glomerular volume increased from 2.63 +/- 0.7 in untreated sham operated to 4.11 +/- 0.48 microm 3 x 10(6) in untreated SNX (56.3%). The glomerulosclerosis index did not change in SNX + PBZ rats, but was significantly lower in SNX + MET (0.56 +/- 0.14) and particularly SNX + PBZ + MET rats (0.49 +/- 0.11) than in untreated SNX (0.74 +/- 0.24). Glomerular capillary length density (LV) as a sensitive index of capillary obliteration was significantly lower in SNX and almost normalized in the three intervention groups. The same was true for the mean podocyte number per glomerulus. Glomerular ultrastructure in SNX was largely preserved by all treatments. The albumin excretion rate was significantly higher in untreated SNX than in sham; it was significantly lower in all treated SNX groups.


CONCLUSIONS
The beneficial effect of non-hypotensive doses of alpha and beta blockers and their combination on renal morphology and albuminuria in the model of renal ablation argue for a blood pressure-independent role of sympathetic overactivity in the genesis of progression. In addition, the beneficial effect of adrenergic receptor blockade indicates that a substantial part is not mediated by sympathetic cotransmitters such as adenosine 5'-triphosphate (ATP) and neuropeptide Y (NPY).
Amann
K
K
Department of Pathology, University of Erlangen, Erlangen, Germany. kerstin.aman@patho.imed.uni-erlangen.de
Koch
A
A
Hofstetter
J
J
Gross
M L
ML
Haas
C
C
Orth
S R
SR
Ehmke
H
H
Rump
L C
LC
Ritz
E
E
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000419:Albuminuria / Q000652:urine; D000818:Animals; D018450:Disease Progression; D004338:Drug Combinations; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology* / Q000652:urine; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D004338:Drug Combinations; D018809:Proliferating Cell Nuclear Antigen