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.

Biomarkers of AKI

“…Given the clearly defined role for the RAS in CKD progression, it is plausible that RAS activation not only modulates the severity of an episode of AKI but also mediates progression to chronic disease. In support of this hypothesis, a study performed using a rat model of AKI and chronic kidney injury shows that spironolactone treatment reduced progression to CKD (72). However, other RAS inhibitors have not been investigated.…”

Astragaloside IV Ameliorates Renal Fibrosis via the Inhibition of Mitogen-Activated Protein Kinases and Antiapoptosis In Vivo and In Vitro

“…4). TGF-b1 has been identified as the most potent and universal growth factor closely associated with fibrosis in various types of models (Doi et al, 2011;Barrera-Chimal et al, 2013). We observed a significant time-dependent increase in the expression of TGF-b1 at the mRNA level (P , 0.05), which was ameliorated by administration of AS-IV after the obstructive injury (P , 0.05) (Fig.…”

“…It has been well established that a-SMA, fibronectin, and collagen IV are hallmarks of myofibroblasts and excessive extracellular matrix accumulation, both of which are increased in various models of chronic injury Ma et al, 2011;Meng et al, 2011;Barrera-Chimal et al, 2013). Basal levels of fibronectin protein and mRNA were barely detected in the sham-operated mice; however, the levels on day 7 were significantly increased and showed additional elevation on day 14 (Fig.…”

25-Hydroxyvitamin D31-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

“…Klotho inhibits epithelial-to-mesenchymal transition, which was implicated in anti-cancerogenous effects of klotho [8,16]. Spironolactone is protective in various models of renal and cardiovascular disease, an effect at least partly independent from lowering of blood pressure [66,67,68,69]. The effects of spironolactone on in vivo Klotho mRNA expression were significant, but minor and presumably cannot fully account for the beneficial effects of spironolactone in various disease models [70].…”