Targeting immune dysfunction during transition from AKI to CKD

Project Summary Acute kidney injury (AKI) significantly increases the risk of developing progressive kidney fibrosis and chronic kidney disease (CKD). T cells and polymorphonuclear neutrophils (PMNs) have been shown involved in pathogenesis of AKI; however, their role(s) during AKI-to-CKD transition remain uncertain. Our recent publication and preliminary data revealed that failure of resolving tubular injury from unilateral ischemia/reperfusion injury (U-IRI, a rapid AKI-to-CKD transition mouse model) led to not only macrophage persistence but also a second wave of T cells and PMNs infiltrating into tubulointerstitium, which closely associated with a proinflammatory milieu. Concomitantly, the tubular cells from U-IRI kidney expressed higher level of injury marker, vascular cell adhesion molecule 1 (Vcam1), and exhibited a dedifferentiated expression profile, correlating with kidney atrophy. Clinically, we found that increasing numbers of T cells and PMNs in the renal interstitium at the time of renal biopsy in patients with AKI negatively correlated with 6-month recovery of GFR. In the U-IRI mouse model, we found that depletion of T cells and PMNs attenuated the second wave of tubular injury and partially restore tubule mass, suggesting that T cells and PMNs promote secondary tubular injury and kidney atrophy, and that blocking T cells and PMNs recruitment can attenuate CKD from AKI. Our chemokine/receptor pair analyses from the scRNA-seq dataset on the IRI kidneys identified that CXCL16 and MCP-2 (Ccl8) are the top homing signals to recruit T cells (CXCR6+) and PMNs (CCR1+) and that persisted macrophages are the primary source of CXCL16 and MCP-2 during AKI-to-CKD transition. Together, these findings have led us to hypothesize that in the setting of failed tubular repair, macrophage-expression of CXCL16 and MCP-2 promotes a second wave of T cells and PMNs infiltrating into the injured kidneys and that tubular VCAM-1 enhances T cells adhesion and retention, which together lead to secondary tubular injury. Thus, targeting the CXCL16/CXCR6 and MCP-2/CCR1 as well as VCAM-1/T cell signaling after kidney injury holds great potential for the treatment of CKD progression. To test this hypothesis, we propose to define the importance of CXCL16/CXCR6 and VCAM-1 signaling in T cell homing and adhesion (SA1) and the importance of MCP-2/CCR1 signaling in PMN homing (SA2) during AKI-to-CKD transition and then to translate our understanding of these homing signals into developing polyamidoamine dendrimer nanoparticles that can selectively deliver siRNAs to knockdown these homing signals to slow or even prevent CKD progression (SA3). This work will provide preclinical data defining how to prevent the second wave of immune activation and transition from AKI to CKD.