0369: Proepicardial Prokineticin Receptor –1 (PKR1) As a Developmental Link Between Heart and Kidney

Prokineticin receptor-1 (PKR1), signals play critical roles in heart and kidney functions. In particular, the systemic mutation of this receptor results in thinning of the myocardium and hypoplastic kidney. However, the molecular and cellular mechanisms controlled by PKR1 signaling in this process are unclear. Here, we analyze a tissue-restricted mutations of the PKR1 gene in the proepicardial lineages (Gata5 and Wt1), and we show that PKR1 signaling in the proepicardium and its derivatives is required for proper cardiac and renal morphogenesis. Neonatal mutant mice display impaired proliferation of epicardial-derived cells in their heart and kidneys. Moreover, we detect defective coronary and renal arteriogenesis associated with PKR1 deficiency. Epicardial development is dramatically impaired in mutant mice, including failed expansion of the subepicardial space, blunted invasion of the myocardium, and impaired differentiation of epicardium-derived cells into coronary endothelial and smooth muscle cells. Abnormal mitochondria, lipid accumulation in mutant cardiomyocytes leads to lower contractile response to dobutamine. Impaired proliferation was observed in both Gata5 and WT1 but apoptosis was observed only WT1 lieage. Adult mutant hearts had abnormal rhythmicity and impaired systolic functions. Hypoplastic kidneys at the neonatal mutants were accompanied with deficient glomerular angiogenesis. Outgrown cell from kidney explants had a defective vasculogenic cell differentiation. Atrophy and dilated glomerular structure, abnormal mitochondria, lipid deposition and apoptosis were observed in the adult mutant kidney. Our findings provide a mechanistic insight into the roles of PKR1 signaling in heart and kidney disorders controlling the maturation of epicardial-derived cell and differentiation in a cell autonomous fashion and affecting cellular communications in a paracrine fashion. Our mouse models recapitulate the complex human heart-kidney disorders.