TIGIT mediates experimental ischemia reperfusion and nephrotoxic acute kidney injury in mice

Abstract

Abstract Background: We unexpectedly found upregulated expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) on kidney CD4 T cells after ischemia reperfusion (IR) using RNA-Seq. However, TIGIT role in kidney T cells and during acute kidney injury (AKI) is poorly understood. Methods: Effect of TIGIT on murine kidney T cells was assessed at baseline and after IR injury by flow cytometry and single cell RNA sequencing (scRNA-Seq). B6 wild type (WT) and TIGIT knockout (KO) mice were subjected to IR and cisplatin-induced AKI. TIGIT expression was assessed in AKI patients using the Kidney Precision Medicine Project (KPMP) scRNA-Seq dataset. Results: We found increased kidney CD4+TIGIT+ central memory (10.0±2.3 vs 0.9±0.1%, p=0.001) cells compared to CD4+TIGIT− cells in WT mice. TIGIT KO mice had reduced serum creatinine (SCr) after IR (24h Scr, 1.1±0.2 vs 2.7±0.1 mg/dL; p≤0.001) and cisplatin (72h Scr, 0.8±0.1 vs 1.4±0.1 mg/dL; p=0.0002) injury compared to WT mice. TIGIT KO kidneys had reduced necrotic tubules in outer medulla after IR (48.8±4.7% vs 73.0±1.5%; p=0.001) and cisplatin (11.5±3.0% vs 31.3±4.0%; p=0.008) injury than WT kidneys. Gene set enrichment analysis of scRNA-Seq data showed enrichment of inflammatory genes in Th17 cells from WT kidney and oxidative phosphorylation and mTORC1 signaling genes in TIGIT KO kidney. Human KPMP data demonstrated significant TIGITexpression in kidney T/NK cells from AKI patients compared to controls (p≤0.0001). Conclusions: TIGIT mediates both IR and nephrotoxic AKI in mice and its expression increases in kidney T cells from AKI patients. TIGIT is a promising novel therapeutic target for AKI, and also relevant due to increasing efforts to develop TIGIT blockade to treat cancers. American Society of Nephrology, Johns Hopkins University Ed Kraus Award, National Kidney Foundation of Maryland and Delaware