Cardiorenal signaling protects from acute kidney injury via ischemic preconditioning, but worsens chronic renal disease

Background Ischemic heart disease is the leading cause of death worldwide. Cardiac dysfunction frequently results in renal dysfunction, a clinical entity known as cardiorenal syndrome. While this is a significant cause of morbidity and mortality, cardiorenal signaling pathways following myocardial ischemia remain poorly understood. Methods Left anterior descending (LAD) artery ligation or sham procedure was performed to induce myocardial infarction (MI) in 9 week‐old male C57/Bl6 mice. Echocardiography was performed using a Vevo 2100 ultrasound machine. Renal ischemia reperfusion injury (IRI) was performed 9 weeks following cardiac surgery via renal pedicle clamping for 30 minutes. The contralateral kidney was removed prior to clamping. For hypoxia studies, mice were maintained in either our standard animal facility (room air), or in a hypoxia chamber for 10 days at 10% FiO2. GFR was measured by transdermal FITC‐sinistrin clearance. Results To study effects of mild MI, independent of severe heart failure, distal LAD artery ligation was performed to cause small, yet statistically significant, reductions in cardiac ejection fraction (88% vs 76%) and fractional shortening (56 % vs 48%) compared to sham controls. Surprisingly, mice that underwent MI were subsequently protected from renal IRI 9 weeks following cardiac surgery. This was shown by reduced weight loss (−13.1% vs −6.1%) and peak BUN (114.3 mg/dL vs 86.9 mg/dL) compared to sham‐operated mice that also underwent IRI. Pre‐IRI total kidney inflammatory markers were increased in the contralateral kidney of mice in the MI group compared with Sham controls. This suggested MI caused renal ischemic preconditioning by affecting the renal inflammatory cell phenotype. To quantify acute effects of MI on renal inflammation, we isolated renal myeloid cells 24 hours following MI or Sham procedure and quantified inflammatory marker mRNA. No differences were detected between MI and Sham groups suggesting a chronic preconditioning process. We therefore hypothesized that MI caused chronic changes in renal oxygen delivery resulting in the observed protection from IRI. Indeed, renal erythropoietin mRNA levels were increased 9 weeks following MI, consistent with this hypothesis. To determine if chronic hypoxia causes ischemic preconditioning, IRI was performed on another group of mice that were maintained in either hypoxic or normoxic conditions. Chronic hypoxia resulted in protection from IRI as shown by decreased weight loss (−16.2% vs 11.9%) and peak BUN (150.0 mg/dL vs 85.4 mg/dL). Despite the acute protection from ischemic renal injury, mice undergoing MI had worsened chronic renal function 5 weeks post‐renal ischemia. This was shown by reduced GFR (903 vs 755 ul/min/100 g BW), increased tubulointerstitial fibrosis as seen by Sirius red staining (0.5% vs 2.8% total area), and increased NGAL staining by IHC (0.03 % vs 0.37% total area) compared to the Sham group that underwent IR. Conclusion Mild‐to‐moderate MI offers protection from acute renal ischemia. Ischemic preconditioning may be mediated by chronic changes in renal oxygen delivery as a similar protective effect was conferred by chronic systemic hypoxia. Despite this acute protective effect, chronic renal damage was worse following MI and IRI compared with IRI alone.