RESUMO
We showed that spironolactone reduced structural damage and prevented renal dysfunction in chronic cyclosporine (CsA) nephrotoxicity. These findings evidenced an aldosterone renal vascular effect under this condition. To investigate aldosterone's role in modulating renal vascular tone, renocortical vasoactive pathways mRNA levels in chronic CsA nephrotoxicity as well as spironolactone's effect on renal function in acute CsA nephrotoxicity were evaluated. Two experimental sets were designed. For chronic nephrotoxicity, rats fed with low-sodium diet were divided into groups receiving vehicle, spironolactone (Sp), CsA, and CsA+Sp, for 21 days. Creatinine clearance, survival percentage, and renocortical mRNA levels of pro-renin, angiotensinogen (Ang), angiotensin receptors (AT(1A), AT(1B), and AT(2)), preproendothelin, endothelin receptors (ET(A), ET(B)), cyclooxygenase-2 (COX-2), and adenosine receptors (Ad(1), Ad(2A), Ad(2B), and Ad(3)) were analyzed. For acute nephrotoxicity, similar groups fed with a standard chow diet for 7 days were included. Serum potassium and sodium, glomerular filtration rate (GFR), and renal blood flow (RBF) were determined. In chronic model, CsA produced pro-renin and ET upregulation, altered adenosine receptors expression, and reduced Ang, AT(1A), AT(1B), ET(B), and COX-2 mRNA levels. Spironolactone protective effect in chronic nephrotoxicity was associated with prevention of pro-renin upregulation and increased AT(2), together with ET(B) reduction. In acute nephrotoxicity, spironolactone completely prevented GFR and RBF reduction induced by CsA. Our results suggest that aldosterone contributes to renal vasoconstriction observed in CsA nephrotoxicity and that renoprotection conferred by spironolactone was related to modification of renocortical vasoactive pathways expression, in which pro-renin normalization was the most evident change in chronic nephropathy. Finally, our data point to spironolactone as a potential treatment to reduce CsA nephrotoxicity in transplant patients.
Assuntos
Aldosterona/fisiologia , Córtex Renal/fisiologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Espironolactona/farmacologia , Animais , Ciclosporina/toxicidade , Imunossupressores/toxicidade , Masculino , Transplante de Órgãos , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores de Endotelina/biossíntese , Sistema Renina-Angiotensina/fisiologiaRESUMO
This study hypothesizes that endothelin-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d). After 20 weeks treatment, rats were killed. Messenger RNA (mRNA) expression of renal preproendothelin-1, endothelin A and B receptors, and procollagen I and III was evaluated by reverse transcription polymerase chain reaction. Expression of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF) was determined by immunoblotting. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography. In salt-loaded SHRSPs, preproendothelin-1 mRNA expression was increased 1.6-fold, and endothelin A receptor mRNA expression was decreased (70% of control). Salt-loaded SHRSPs had increased renal expression of TGF-b1 and procollagens. MMP-2 activity was augmented fivefold. BMS decreased (p < 0.01) expression of TGF-beta1, bFGF, and procollagen I and reduced MMP-2 activity. Thus severe hypertension and renal dysfunction in salt-loaded SHRSPs are associated with increased expression of renal endothelin-1, growth factors, and collagen. BMS treatment alleviated these effects, suggesting that nephroprotection by endothelin A receptor blockade is mediated by normalizing expression of growth factors, reducing extracellular matrix deposition, and decreasing MMP activity.