Blood pressure and the susceptibility to renal damage after unilateral nephrectomy and L-NAME-induced hypertension in rats.
BACKGROUND
Fawn-hooded hypertensive (FHH) rats carry several genes which determine the susceptibility to develop renal damage, while renal damage resistant August x Copenhagen Irish (ACI) rats do not. Kidneys from heterozygous (FHH x ACI) F(1) rats, appear to be largely, but not completely, protected after blood pressure elevation with N(omega)-nitro-L-arginine methyl ester (L-NAME). We examined the role of an increased haemodynamic burden on the development of renal damage combining unilateral nephrectomy (UNx)- and L-NAME-induced hypertension in F(1) and ACI rats. Additionally, we investigated whether a general toxic effect of L-NAME, independent from a blood pressure elevation, caused renal damage in F(1) rats in animals simultaneously treated with L-NAME and the ACE inhibitor lisinopril.


METHODS
Surgery was performed and L-NAME treatment (50 or 150 mg/l) was started at the age of 15 weeks. Systolic blood pressure (SBP) and urinary albumin excretion (UaV) were measured at 6 and 12 weeks post-UNx, followed by autopsy to determine the incidence of focal glomerulosclerosis (FGS). Using lisinopril (LIS) and L-NAME, another group of rats was evaluated at 12, 18, and 24 weeks after start of treatment.


RESULTS
At similar L-NAME intake, F, rats developed more severe hypertension and more UaV than ACI rats. The increase in UaV per mmHg increase in SBP was fivefold higher in F(1) compared with ACI rats. In F(1) rats, the increase in UaV per percentage incidence increase in FGS was three times higher. In LIS treated F(1) rats, no significant UaV or FGS was measured at low blood pressure levels, indicating that renal damage in hypertensive F(1) rats is not a direct effect of L-NAME, but the result of the high blood pressure or another action of the renin-angiotensin system.


CONCLUSIONS
We conclude that heterozygosity for the genes influencing the development of renal damage in the FHH strain increases the susceptibility of the kidney to develop damage after UNx combined with systemic hypertension.
van Dokkum
R P
RP
Department of Pediatric Surgery, Erasmus University Medical School, Rotterdam, The Netherlands.
Jacob
H J
HJ
Provoost
A P
AP
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D001794:Blood Pressure; D004791:Enzyme Inhibitors; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology* / Q000652:urine; D066298:In Vitro Techniques; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester; D009392:Nephrectomy / Q000379:methods*; D011184:Postoperative Period; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics; D012044:Regression Analysis; D013599:Systole
D004791:Enzyme Inhibitors; D019331:NG-Nitroarginine Methyl Ester