Effect of enalapril and losartan on the events that precede diabetic nephropathy in rats.
BACKGROUND
Mesangial cell proliferation, phenotype change, and increased transforming growth factor-beta (TGF-beta) precede mesangial expansion in diabetic rats. Experiments using mesangial cell culture have shown that angiotensin II increases TGF-beta production by these cells. The aim of the present study was to investigate the effect of enalapril and losartan on the events that precede diabetic nephropathy in rats. It was also analyzed if the determination of urinary TGF-beta could be a mean for the evaluation of therapeutic efficacy in this disease.


METHODS
Eighty-two female Wistar rats were made diabetic by intravenous injection of streptozotocin diluted in citrate buffer, and citrate buffer alone was injected into the control group (N = 34). Ten days later, the right kidney was removed. Thirty diabetic rats were treated with enalapril, DMN + E, in drinking water (20 mg/L) and 24 with losartan, DMN + L (50 mg/L). Urinary TGF-beta was determined 90 days after STZ or buffer injection, the animals were killed, and the kidneys were removed for histological and immunohistochemical studies.


RESULTS
The immunostaining for TGF-beta and fibronectin in the cortical tubulointerstitium and glomeruli was higher in untreated diabetic rats (p < 0.001). Treatment with enalapril or losartan reduced this increase. The urinary TGF-beta excretion (pg/mg urinary creatinine) was 48.6 +/- 5.9 in control animals, 603.9 +/- 80.41 in untreated diabetic rats, 279.3 +/- 47.0 in diabetic rats treated with enalapril, and 243.7 +/- 40.0 in rats treated with losartan.


CONCLUSIONS
We concluded that enalapril or losartan treatment can modify events that precede diabetic nephropathy by reducing TGF-beta and fibronectin expression in glomeruli and tubulointerstitium as well as urinary TGF-beta content.
Volpini
Rildo Aparecido
RA
Department of Physiology, Medical School of Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
da Silva
Cleonice Giovanini Alves
CG
Costa
Roberto Silva
RS
Coimbra
Terezila Machado
TM
D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000652:urine; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D004656:Enalapril / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D011236:Prediabetic State / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000652:urine*; D053773:Transforming Growth Factor beta1
D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D005353:Fibronectins; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004656:Enalapril; D019808:Losartan