Angiotensin (1-7) protects against renal ischemia-reperfusion injury via regulating expression of NRF2 and microRNAs in Fisher 344 rats

Ischemia-reperfusion (I/R) is considered the primary cause of acute kidney injury and is higher among older individuals. Although ischemic episodes are hard to predict and prevent, detrimental ischemic effects could be mitigated by exogenous intervention. This study aimed to identify the protective role of angiotensin (1???7) [ANG(1???7)] against I/R-induced renal injury in adult versus aged rats. Adult and aged male Fisher 344 rats were subjected to 40 min of bilateral renal ischemia followed by 28 days of reperfusion. ANG(1???7) was administered intraperitoneally in ischemic rats for 28 days with or without the Mas receptor antagonist A779. I/R increased blood pressure, plasma creatinine, urinary 8-isoprostane, and renal infiltration of pro- and anti-inflammatory macrophages and reduced glomerular filtration rate in both adult and aged rats compared with sham rats. In addition to causing glomerular sclerosis and tubular damage, I/R increased the expression of the following pathogenic miRNAs: miR-20a-5p, miR-21-5p, miR-24-3p, and miR-194-5p in both age groups. ANG(1???7) treatment of ischemic rats mitigated oxidative stress and renal inflammation, restored renal structure and function, and reduced high blood pressure. Also, ANG(1???7) suppressed the expression of pathogenic miRNAs. In addition, ANG(1???7) treatment of I/R rats increased the expression of the redox-sensitive transcription factor nuclear factor-erythroid factor 2-related factor 2 (NRF2) and phase II antioxidant enzymes. The beneficial effects of ANG(1???7) were sensitive to A779. Collectively, these data suggest that ANG(1???7) associated with NRF2 activation could alleviate post-I/R-induced kidney injury, and therefore serve as a potential therapeutic compound to protect against biochemical and morphological pathologies of I/R in both adults and aged populations. NEW & NOTEWORTHY This is the first study to show that ANG(1???7) via Mas receptors could activate the redox-sensitive nuclear factor-erythroid factor 2-related factor 2 (NRF2)-phase II antioxidant system and protect against ischemia-reperfusion (I/R)induced renal injury, identifying ANG(1???7), Mas receptor agonists, or NRF2 activators as potential therapeutic interventions to protect against renal and cardiovascular diseases. Moreover, miRNAs have differential expression in adult versus aged rats, and I/R modulates miRNA expression in both age groups, indicating their involvement in kidney disease.