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Renocortical mRNA expression of vasoactive factors during spironolactone protective effect in chronic cyclosporine nephrotoxicity

Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexcio City, Mexico

Submitted 20 April 2005 ; accepted in final form 28 June 2005

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 AT₂), preproendothelin, endothelin receptors (ET_A, ET_B), cyclooxygenase-2 (COX-2), and adenosine receptors (Ad₁, Ad_2A, Ad_2B, and Ad₃) 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 AT₂, 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.

renin; AT₂ receptors; COX-2; acute CsA nephrotoxicity

This article has been cited by other articles:

				N. A. Bobadilla and G. Gamba New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone Am J Physiol Renal Physiol, July 1, 2007; 293(1): F2 - F9. [Abstract] [Full Text] [PDF]

				J. M. Mejia-Vilet, V. Ramirez, C. Cruz, N. Uribe, G. Gamba, and N. A. Bobadilla Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone Am J Physiol Renal Physiol, July 1, 2007; 293(1): F78 - F86. [Abstract] [Full Text] [PDF]

				J. Perez-Rojas, J. A. Blanco, C. Cruz, J. Trujillo, V. S. Vaidya, N. Uribe, J. V. Bonventre, G. Gamba, and N. A. Bobadilla Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity Am J Physiol Renal Physiol, January 1, 2007; 292(1): F131 - F139. [Abstract] [Full Text] [PDF]