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Int J Biol Sci 2015; 11(8):892-900. doi:10.7150/ijbs.11729

Research Paper

Mild ischemic Injury Leads to Long-Term Alterations in the Kidney: Amelioration by Spironolactone Administration

Jonatan Barrera-Chimal1,2,4, Rosalba Pérez-Villalva1,2, Juan Antonio Ortega1,2, Andrea Sánchez1,2, Roxana Rodríguez-Romo1,2, Marta Durand3, Frederic Jaisser4, Norma A. Bobadilla1,2✉

1. Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México
2. Nephrology Department of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
3. Reproductive Biology Department of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
4. INSERM U1138, Centre de Recherche de Cordeliers, Team 1, Paris, France

Abstract

Administration of the mineralocorticoid receptor antagonist spironolactone prevents the development of chronic kidney disease (CKD) after a severe ischemic injury. However, whether brief periods of ischemia lead to CKD and whether spironolactone administration after ischemia may be a useful therapeutic strategy to prevent the gradual deterioration of structure and function remains unexplored.

Nineteen male Wistar rats were divided into four groups: rats that underwent renal bilateral ischemia for 10, 20, or 45 min were compared with sham operated rats. Additionally, thirteen male Wistar rats that underwent renal bilateral ischemia for 20 min were divided into an untreated ischemic group (I) and two groups receiving spironolactone, 20 mg/kg by gavage, at either 0 (Sp0) or 1.5-h after ischemia (Sp1.5). The rats were followed up and studied after 9 months.

Mild (20 min) and severe (45 min) ischemia induced a progressive increase in proteinuria at varying magnitudes, whereas minor ischemia (10 min) did not modify proteinuria. CKD induced by moderate ischemia was characterized by renal hypertrophy and tubulointerstitial fibrosis. These effects were associated with activation of the transforming growth factor β (TGFβ) signaling pathway and up-regulation of endothelin receptor A (ETA) and alpha smooth muscle actin (αSMA). Spironolactone treatment immediately or 1.5-h after the ischemic insult prevented the onset of these disorders.

Our results show that moderate ischemic insult leads to long-term structural and molecular changes that may compromise renal function in later stages. Additionally, we demonstrate that spironolactone administration after mild ischemia prevents this detrimental effect.

Keywords: Aldosterone, fibrosis, acute kidney injury, chronic kidney disease

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How to cite this article:
Barrera-Chimal J, Pérez-Villalva R, Ortega JA, Sánchez A, Rodríguez-Romo R, Durand M, Jaisser F, Bobadilla NA. Mild ischemic Injury Leads to Long-Term Alterations in the Kidney: Amelioration by Spironolactone Administration. Int J Biol Sci 2015; 11(8):892-900. doi:10.7150/ijbs.11729. Available from http://www.ijbs.com/v11p0892.htm