AT-1 receptor blockade prevents proteinuria, renal failure, hyperlipidemia, and glomerulosclerosis in the Imai rat.
BACKGROUND
The Imai rat is a model of spontaneous focal glomerulosclerosis which leads to nephrotic syndrome, hyperlipidemia, hypertension, and progressive renal failure. We evaluated the effects of angiotensin II receptor type 1 (AT-1)blockade, and compared the results with the effects of the administration of hypolipidemic treatment with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. All treatments were started at 10 weeks of age when the rats were already proteinuric and continued for 6 months when rats were sacrificed.


METHODS
The following groups (N= 6 each) were studied: (1) control Sprague-Dawley rats, 34 weeks old; (2) Imai group that received vehicle; (3) Imai + angiotensin II receptor blockade (ARB) group that received olmesartan (10 mg/kg/day by gastric gavage); (4) Imai + prava group, that received pravastatin (20 mg/kg/day by gastric gavage); and (5) Imai + ARB + prava group that received both ARB and pravastatin. Lipid profile, renal function, and structure were assessed at 6 months.


RESULTS
As expected, the untreated Imai rats exhibited heavy proteinuria, hypoalbuminemia, hypertension, renal insufficiency, marked glomerulosclerosis, tubulointerstitial inflammation, and profound hyperlipidemia. Pravastatin treatment alone led to a significant, but partial improvement of hyperlipidemia and renal disease. The ARB treatment alone or in combination with pravastatin resulted in normalization of the blood pressure, urinary protein excretion, plasma cholesterol, triglycerides, low-density lipoproteins (LDLs), very low-density lipoproteins (VLDLs), and albumin concentrations and renal function. Significant glomerulosclerosis was prevented and tubulointerstitial injury and immune cell infiltration were reduced by long-term AT-1 blockade.


CONCLUSIONS
The study revealed that long-term AT-1 blockade corrects proteinuria, hyperlipidemia, and nephropathy in this model of spontaneous glomerulosclerosis.
Rodríguez-Iturbe
Bernardo
B
Hospital Universitario, Universidad del Zulia and Instituto de Investigaciones Biomédicas, Maracaibo, Venezuela. bri@iamnet.com
Sato
Tadashi
T
Quiroz
Yasmir
Y
Vaziri
Nosratola D
ND
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015243:Cholesterol, VLDL / Q000097:blood; D004359:Drug Therapy, Combination; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006949:Hyperlipidemias / Q000188:drug therapy / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D000068557:Olmesartan Medoxomil; D017035:Pravastatin / Q000494:pharmacology; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D015243:Cholesterol, VLDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; D014280:Triglycerides; D000068557:Olmesartan Medoxomil; D017035:Pravastatin