#1116 Pericytes mediate renal recovery after acute kidney injury through CXCL12

Abstract Background and Aims Acute kidney injury (AKI) causes various complications, including the need for kidney replacement therapy (KRT), progression to chronic kidney disease (CKD), and increased risk of death. Pericytes, mesenchyme-derived perivascular cells, are thought to play a protective role following AKI. Our previous studies demonstrated that pericytes become activated and differentiate into myofibroblasts in animal models of unilateral ureteral obstruction and ischemia-reperfusion injury (IRI). Furthermore, we found that inhibiting pericytes during IRI-induced AKI resulted in decreased expression of the C-X-C motif chemokine 12 (CXCL12) gene. CXCL12 has been shown to play a critical role in the recovery from organ injury. However, the role of CXCL12 and its underlying mechanisms in AKI remain poorly understood. Method In human study, we measured the plasma levels of CXCL12 of critical ill patients with AKI. In animal study, we used Gli1CreERT2/+;iDTR mice to ablate pericytes. Additionally, we utilized Gli1CreERT2/+; Cxcl12F/F and Tg(UBC-CreERT2); Cxcl12F/F mice to conditionally knock out CXCL12/SDF-1 specifically in pericytes or globally prior to IRI. In vitro, we treated a mouse tubular cell line with recombinant CXCL12 protein. Results In the human study, we found that plasma levels of CXCL12 were elevated in critically ill patients with AKI. In the animal study, we demonstrated that CXCL12 was primarily secreted by pericytes, while its receptors, CXCR4 and CXCR7, were expressed on tubular cells during IRI, as shown by in situ hybridization. Furthermore, we discovered that pericyte ablation during IRI-induced AKI worsened tubular cell proliferation, leading to poorer recovery of renal function. Both pericyte-specific and global knockout of CXCL12/SDF-1 impaired renal function recovery after IRI-AKI through mechanisms including renal microvascular rarefaction, reduced proliferation, and increased apoptosis in renal tubular cells. In vitro, CXCL12 was found to stimulate proximal tubular cell proliferation and growth factor production via activation of the PI3K/Akt signaling pathway in both proximal and distal tubular cells. Conclusion CXCL12 levels increased after AKI and were primarily expressed in renal pericytes, which contribute to renal repair following IRI. CXCL12 activated the PI3K/Akt signaling pathway, stimulating proliferation and growth factor production in renal tubular cells during IRI-AKI.