Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury

• DOI: 10.1038/ki.2012.352
• Publication Date: 2012-09-26T12:53:26Z
• Authors: Jonatan Barrera-C...; Rosalba Pérez-Vil...; Roxana Rodríguez-...; Juan Reyna; Norma Uribe; Gerardo Gamba; Norma A. Bobadilla
• Keywords: Male; 0301 basic medicine; inflammatory cytokines; Spironolactone; Kidney; Collagen Type I; 03 medical and health sciences; Ischemia; Transforming Growth Factor beta; oxidative stress; Animals; mineralocorticoid receptor blockade; tubular proliferation; Rats, Wistar; Renal Insufficiency, Chronic; Diuretics; Mineralocorticoid Receptor Antagonists; Dose-Response Relationship, Drug; Acute Kidney Injury; Fibronectins; Rats; 3. Good health; Disease Models, Animal; Oxidative Stress; Nephrology; TGF-β pathway

Acute kidney injury (AKI) has been recognized as a risk factor for the development of chronic kidney disease (CKD). Aldosterone has a critical role in promoting renal injury induced by ischemia. Here, we evaluated whether spironolactone administered before or after AKI caused by ischemia protects against CKD. In the first set of experiments, Wistar rats underwent a sham operation without or with prior spironolactone treatment, or underwent 45 minutes of bilateral renal ischemia without or with spironolactone treatment before ischemia and assessed over 270 days. The second set of rats received low (20 mg/kg) or high (80 mg/kg) doses of spironolactone at three different times after the sham operation or bilateral renal ischemia and were assessed after 90 days. Untreated animals developed CKD following ischemia-induced AKI as characterized by a progressive increase in proteinuria, renal dysfunction, podocyte injury, glomerular hypertrophy, and focal sclerosis. This was associated with increased oxidative stress, an upregulation of tumor growth factor (TGF)-β, followed by upregulation of the TGF-β downstream effectors phospho-Smad3, collagen I, fibronectin, and proinflammatory cytokines. Treatment with spironolactone either before or after ischemia prevented subsequent CKD by avoiding the activation of fibrotic and inflammatory pathways. Thus, spironolactone may be a promising treatment for the prevention of AKI-induced CKD.