Glomerular basement membrane anionic sites in adriamycin nephropathy: effect of saline loading and nitric oxide modulation.
BACKGROUND
In previous studies we found that experimental Adriamycin (ADR) nephropathy is associated with the loss of glomerular basement membrane (GBM) anionic sites provided by heparan sulfate proteoglycans. Chronic saline loading in normal rats resulted in a similar effect on the GBM anionic sites. The L-arginine-nitric oxide synthase-nitric oxide system is involved in the pathogenesis of experimental chronic renal failure. The present study was performed to determine the combined effect of nitric oxide (NO) modulation and chronic saline loading in ADR nephropathy. The modulation of NO was done by chronic administration of L-arginine (NO donor) or N(w)-nitro-L-arginine, a known nitric oxide synthase inhibitor.


METHODS
Systolic blood pressure was measured in awake rats by a tail-cuff method. Renal function was assessed by creatinine clearance, FeNa%, and daily protein excretion. The change of mean GBM widths and anionic sites distribution were assessed by electron microscopy. The localization of anionic sites was carried out by cationic colloidal gold. Plasma and urinary nitrates (NO(x)) were measured by nitrite (NO(2)) + nitrate (NO(3)), stable metabolites of NO.


RESULTS
Two weeks after the ADR administration (3.5 mg/kg BW iv) the rats had severe renal failure (creatinine clearance 134 +/- 31 microl/min/100 g BW vs. initial values 670 +/- 29 microl/min/ 100 g BW, p < 0.001), high FeNa%, severe proteinuria, increased GBM width, significant reduction of GBM anionic sites and low urinary NO(x) excretion. The saline loading resulted in further reduction of GBM anionic sites count and blood pressure elevation. The inhibition of NO did not change the course of ADR nephropathy. The main finding of the present study is that chronic administration of L-arginine significantly alleviates the renal failure in the ADR (+/- saline loading) nephropathy. The L-arginine-treated rat had higher creatinine clearance, lower FeNa% and protein excretion and complete normalization of GBM anionic sites distribution.


CONCLUSIONS
Sodium loading has a deleterious effect on GBM permselectivity. L-Arginine prevents the reduction of GBM anionic sites, decreases proteinuria and alleviates the renal insufficiency in ADR nephropathy.
Hertzan-Levy
S
S
Department of Nephrology, Ichilov, Tel-Aviv and Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel.
Fish
R
R
Skutelsky
E
E
Wollman
Y
Y
Chernichovsky
T
T
Polak-Charcon
S
S
Schwartz
D
D
Blum
M
M
Cabili
S
S
Iaina
A
A
D000818:Animals; D000838:Anions; D001120:Arginine / Q000494:pharmacology; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D004317:Doxorubicin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017979:Gold Colloid / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride
D000838:Anions; D004791:Enzyme Inhibitors; D017979:Gold Colloid; D019812:Heparan Sulfate Proteoglycans; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D019335:Nitroarginine; D009569:Nitric Oxide; D012965:Sodium Chloride; D004317:Doxorubicin; D001120:Arginine; D019001:Nitric Oxide Synthase