Loss of Renal Pericyte Vascular Endothelial Growth Factor Receptor 2 (VEGF-R2) Protects Against AKI-to-CKD Transition

Background: Acute kidney injury (AKI) increases the risk of developing chronic kidney disease (CKD), yet no therapies remain unavailable. A key pathological feature of AKI is injury to the renal microvasculature, including endothelial cells and pericytes, inducing maladaptive fibrotic signaling cascades. Pericytes, a heterogeneous mesenchymal population, are a major source of myofibroblasts, the key drivers of fibrosis. While vascular endothelial growth factor receptor 2 (VEGF-R2) is known as a master regulator of angiogenesis in endothelial cells, it also negatively regulates angiogenesis in pericytes. Previously, we preliminary demonstrated that constitutive knockout of VegfR2 in renal stromally derived cells, including pericytes, mitigates the AKI-to-CKD transition. However, this mouse model may be confounded by developmental effects inherent to constitutive knockout approaches, or the observed effects may originate from other stromally derived cell types, such as podocytes, rather than pericytes specifically. We hypothesized that renal pericyte-specific VEGF-R2 signaling impairs microvascular recovery and promotes AKI-to-CKD progression. Understanding this maladaptive crosstalk may reveal novel therapeutic targets. Methods: We generated genetic mouse models with renal stromal cell (RSC)- or pericyte (PC) specific deletion of VegfR2 using both tamoxifen-inducible Cre drivers (Foxd1-CreERT2 and Pdgfrb-CreERT2), referred to as iVegfR2RSC–-/ and iVegfR2PC–-/–. To investigate the role of VegfR2 signaling in renal pericytes during AKI-to-CKD transition, mice underwent unilateral ureteral obstruction (UUO)-induced CKD model. The degree of fibrosis following UUO was assessed using Masson's trichrome staining and real-time qPCR analysis of fibrosis markers, including Acta2 and Col1a1. Results: Tamoxifen-pretreated iVegfR2RSC–-/ and iVegfR2PC–-/– kidneys consistently exhibited protection against UUO-induced CKD, as evidenced by reduced fibrosis in Masson’s trichrome-stained sections and decreased expression of fibrosis markers. Conclusion: These findings further suggest that loss of VEGF-R2 in renal pericytes mitigates CKD progression.