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.

Despite clinical recovery of patients from an episode of acute kidney injury (AKI), progression to chronic kidney disease (CKD) is possible on long-term follow-up. However, mechanisms of this are poorly understood. Here, we determine whether activation of angiotensin-II type 1 receptors during AKI triggers maladaptive mechanisms that lead to CKD. Nine months after AKI, male Wistar rats develop CKD characterized by renal dysfunction, proteinuria, renal hypertrophy, glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis. Renal injury was associated with increased oxidative stress, inflammation, α-smooth muscle actin expression, and activation of transforming growth factor β; the latter mainly found in epithelial cells. Although administration of losartan prior to the initial ischemic insult did not prevent or reduce AKI severity, it effectively prevented eventual CKD. Three days after AKI, renal dysfunction, tubular structural injury, and elevation of urinary biomarkers were present. While the losartan group had similar early renal injury, renal perfusion was completely restored as early as day 3 postischemia. Further, there was increased vascular endothelial growth factor expression and an early activation of hypoxia-inducible factor 1 α, a transcription factor that regulates expression of many genes that help reduce renal injury. Thus, AT1 receptor antagonism prior to ischemia prevented AKI to CKD transition by improving early renal blood flow recovery, lesser inflammation, and increased hypoxia-inducible factor 1 α activity.

This study evaluated if there is a sexual dimorphism in the acute kidney injury (AKI) to chronic kidney disease (CKD) transition and the time-course of the potential mechanisms involved in the dimorphic response. Female and male rats were divided into sham-operated or underwent 45-min renal ischemia (F + IR, and M + IR). All groups were studied at 24-h and 1, 2, 3, or 4-months post-ischemia. Additionally, oophorectomized rats were divided into sham or IR groups. After 24-h, AKI extent was simllar in females and males, but female rats exhibited less oxidative stress and increased renal GSH content. After 4-months and despite similar AKI, the M + IR group developed CKD characterized by proteinuria, tubulointerstitial fibrosis, glomerular hypertrophy, increased oxidative stress and a reduction in HIF1α and VEGF from the 1st-month and persisting throughout the time-course studied. Interestingly, the F + IR group did not develop CKD due to lesser oxidative stress and increased eNOS, TGFβ and HIF1α mRNA levels from the 1st-month after IR. Whereas, oophorectomized rats did develop CKD. We found a sexual dimorphic response in the AKI to CKD transition. Early antioxidant defense and higher TGFβ, HIF1α and eNOS were among the renoprotective mechanisms that the F + IR group demonstrated.