title: Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury.
abstract: 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.
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Barrera-Chimal
authors.forename: Rosalba
authors.initials: R
authors.lastname: Pérez-Villalva
authors.forename: Roxana
authors.initials: R
authors.lastname: Rodríguez-Romo
authors.forename: Juan
authors.initials: J
authors.lastname: Reyna
authors.forename: Norma
authors.initials: N
authors.lastname: Uribe
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
authors.forename: Norma A
authors.initials: NA
authors.lastname: Bobadilla
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D004232:Diuretics; D005353:Fibronectins; D000451:Mineralocorticoid Receptor Antagonists; D016212:Transforming Growth Factor beta; D013148:Spironolactone