Acute cardiorenal syndrome (cardiorenal syndrome type 1, CRS1) frequently follows the most common cause of admission to a Veterans Health Administration inpatient facility, acute cardiovascular disease. Although CRS1 seems to self-resolve in most cases, development of chronic kidney disease often occurs rapidly afterward (within 1-2 years). Animal studies demonstrate there is mechanistic connection between CRS1 and early onset CKD, a form of AKI-CKD transition. The long term goal is to determine mechanisms of long-term outcomes of CRS1 with a focus on the potential for translational intervention. The proposed work is focused on whether and how CRS1 induces further cardiovascular disease commonly comorbid with CKD. Published data generated in a mouse model of CRS1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) demonstrate that despite recovery of renal function 2 weeks after CA/CPR, CKD ubiquitously occurs by 7 weeks after CA/CPR. Data generated for this proposal show that 7 weeks after CA/CPR, mice have developed systemic hypertension with associated changes in renal vascular architecture and myocardial wall thickness. Tantalizingly, CKD and systemic hypertension are recapitulated by injection of a soluble cardiac- derived factor, CSRP3, which is released into the plasma after CA/CPR. CSRP3 functions as transcriptional activator of the myogenesis pathway in cardiac development. Data suggest that CSRP3 mediates the renin- angiotensin system through angiotensin-converting enzyme 2 (ACE2) in the renal proximal tubule. Therefore the central hypothesis in this proposal is acute cardiorenal syndrome causes chronic systemic hypertension via CSRP3-induced, myogenesis-mediated reduction of proximal tubule ACE2 activity. The specific hypothesis is that that the myogenesis factor MyoD is induced in proximal tubule epithelial cells by CSRP3 exposure, and in turn represses ACE2 membrane distribution. This hypothesis will be investigated in two specific aims. Aim 1 will determine the mechanism by which CRS1 causes chronic systemic hypertension in vivo. Wild-type mice, and mice with inducible, cardiac-specific deletion of CSRP3, or deletion of proximal tubule ACE2 will be subjected to CA/CPR. It is hypothesized that in the absence of cardiac CSRP3, hypertension will be blunted, while in the absence of ACE2 in the proximal tubule, hypertension will be exacerbated. Blood pressure will be assessed in awake, unrestrained mice 7 weeks after CA/CPR using radiotelemetry, and renal function, myogenesis determination genes, and components of the renin-angiotensin system including ACE2 will be assessed using qPCR, immunoblotting, and renal immunofluorescence. Heart and kidney sections will be assessed to determine whether myocardial wall thickness and renal arcuate arterial wall thickness are altered. Translational experiments will determine plasma CSRP3 levels in deidentified patients with cardiac disease, and test whether pharmacologic inhibition of CSRP3 u...