Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone (original) (raw)

2007, AJP: Renal Physiology

Renal ischemia and reperfusion (I/R) injury is the major cause of acute renal failure and may also be involved in the development and progression of some forms of chronic kidney disease. We previously showed that a mineralocorticoid receptor (MR) blockade prevents renal vasoconstriction induced by cyclosporine that leads to acute and chronic renal failure (8; 32). Thus, we investigated whether spironolactone administration prevents the functional and structural damage induced by renal ischemia/reperfusion (I/R). Five groups were studied: sham operated animals, rats underwent 20 min of ischemia and 24 h of reperfusion, and three groups received spironolactone 1, 2 or 3 days before I/R, respectively. Renal I/R produced significant renal dysfunction and tubular damage. Spironolactone administration completely prevented decrease in renal blood flow, the development of acute renal failure, and tubular apoptosis. The protection conferred by spironolactone was characterized by decreasing oxidative stress, as evidenced by a reduction in kidney lipoperoxidation, increasing expression of antioxidant enzymes, and restoration of urinary NO 2 /NO 3 excretion. Endothelial nitric oxide synthase expression was up-regulated by a MR blockade in I/R groups, in addition an increase in activating phosphorylation of this enzyme at residue S1177 and a decrease in inactivating phosphorylation at T497 was observed. In conclusion, our study shows that spironolactone administration prevents the renal injury induced by ischemia/reperfussion, suggesting that aldosterone plays a central role in this model of renal injury. NA. Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity. Kidney Int 63: 43-52, 2003. 9. Fiebeler A, Schmidt F, Muller DN, Park JK, Dechend R, Bieringer M, Shagdarsuren E, Breu V, Haller H and Luft FC. Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. Hypertension 37: 787-793, 2001. 10. Friedewald JJ and Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int 66: 486-491, 2004. 11. Goligorsky MS, Brodsky SV and Noiri E. NO bioavailability, endothelial dysfunction, and acute renal failure: new insights into pathophysiology. Semin Nephrol 24: 316-323, 2004. 12. Gros R, Ding Q, Armstrong S, O'neil C, Pickering JG and Feldman RD. Rapid effects of aldosterone on clonal human vascular smooth muscle cells. Am DR. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 17: 1362-1372, 2006. 14. Henry R.J., Sobel Ch and Segalove M. Turbidimetric determination of proteins with sulfoasalicylic and tricholoroacetic acid. Proc Soc Exp Biol Med 92: 748-751, 1956. Page 21 of 35 15. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 66: 1-9, 2004. 16. Hostetter TH and Ibrahim HN. Aldosterone in chronic kidney and cardiac disease. J Am Soc Nephrol 14: 2395-2401, 2003. 17. Jassem W and Heaton ND. The role of mitochondria in ischemia/reperfusion injury in organ transplantation. Kidney Int 66: 514-517, 2004. 46. Versteilen AM, Korstjens IJ, Musters RJ, Groeneveld AB and Sipkema P. Rho kinase regulates renal blood flow by modulating eNOS activity in ischemiareperfusion of the rat kidney. Am J Physiol Renal Physiol 291: F606-F611, 2006. 47. Virdis A, Neves MF, Amiri F, Viel E, Touyz RM and Schiffrin EL. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 40: 504-510, 2002. 48. Weight SC, Bell PR and Nicholson ML. Renal ischaemia--reperfusion injury. Br J Surg 83: 162-170, 1996. 49. Wellwood JM, Price RG, Ellis BG and Thompson AE. A note on the practical aspects of the assay of N-acetyl-beta-glucosaminidase in human urine. Clin Chim Acta 69: 85-91, 1976. 50. Wijsman JH, Jonker RR, Keijzer R, van de Velde CJ, Cornelisse CJ and van Dierendonck JH. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J Histochem Cytochem 41: 7-12, 1993. 51. Yamasowa H, Shimizu S, Inoue T, Takaoka M and Matsumura Y. Endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning.