Loss of Vascular Endothelial Growth Factor Receptor 2 (VEGF-R2) in the Renal Stroma Regulates Lipid Metabolism to Halt AKI-to-CKD Transition

Background: A dire consequence of acute kidney injury (AKI) is a dramatically increased risk of developing chronic kidney disease (CKD). Understanding the mechanisms by which AKI progresses to CKD is essential for the development of therapies, for which none currently exist. The renal microvasculature, including pericytes and endothelial cells, is damaged in AKI, leading to recruitment of inflammatory cells that contribute to progression to CKD. Pericytes are a heterogeneous mesenchymal population and have been identified as a major source of myofibroblasts that drive CKD. Interestingly, VEGF-R2 (known as the master regulator of angiogenesis for endothelium) acts as a negative regulator of pericytes limiting angiogenesis in vitro. Understanding the molecular mechanisms that mediate maladaptive endothelial-pericyte crosstalk leading to exacerbated and prolonged inflammation may facilitate therapeutic exploitation of this phenomenon. Methods: We generated genetic mouse models for renal stromal cell (RSC)-specific loss-of-function of VegfR2 with Foxd1-Cre (VegfR2RSC-/-) to interrogate the role of VegfR2 in the renal stroma, which includes pericytes, in the AKI-to-CKD transition. Mice were subjected to three CKD models induced by either renal ischemia/reperfusion injury (IRI), low/repeated cisplatin treatment, or unilateral urethral obstruction (UUO). Results: Our RNA-seq analysis of isolated renal stroma with or without renal IRI revealed that injured renal RSCs decreased the expression of genes associated with lipid metabolism. We found that VegfR2RSC-/- mice consistently mitigated AKI-to-CKD transition in all three CKD models (IRI, UUO, and cisplatin). VegfR2RSC-/- mice have reduced inflammation, oxidative stress as well as reduced interstitial lipid deposition after renal IRI. Mechanistically, VegfR2RSC-/- kidneys have increased expression of a lipid metabolism associated genes, Bnip3 and Pyruvate dehydrogenase kinase1 (PDK1), contributing to the enhanced protection. Conclusion: These data suggest that loss of VEGF-R2 in the renal stroma reduces oxidative stress and lipid metabolism to attenuate inflammation to halt CKD. Funding: NIDDK Support