Abstract P319: Genetic Interactions Between Novel Genes Arhgef11 And Cgnl1 Are Involved In Hypertensive Chronic Kidney Disease

Patients with hypertension are at higher risk for developing chronic kidney disease (CKD) and ultimately kidney failure. Previous genetic studies involving the Dahl salt-sensitive (SS) rat, a well-established model of hypertensive CKD, identified multiple regions linked to kidney injury. Extensive work on Chr.2 identified and characterized the role of Arhgef11 in the onset and progression of CKD using SS- Arhgef11 -/- rats. The identification of Arhgef11 and mechanism (regulation of actin cytoskeleton components) has provided an opportunity to expedite gene identification on other chromosomes based on known genetic interactions between loci, such as with Chr. 8. The effect of the Chr. 8 locus on kidney injury was previously validated using a congenic strain [S.SHR(8)]. Bioinformatics analysis of genes residing within the confidence interval, and those mechanistically linked with Arhgef11 , identified cingulin-like 1 ( Cgnl1 ) as a candidate. Cgnl1 plays a role in the regulation of cell-cell contacts via adherens and tight junctions through several interacting proteins [e.g. ZO-1 and PLEKHA7 (linked with hypertension by GWAS and an SS- Plekha7 mutant model)]. Recent studies using a novel model (SS- Cgnl1 -/- ) demonstrates that knockout of Cgnl1 leads to loss of salt-sensitive blood pressure and reduced renal injury compared to wildtype SS, supporting the congenic studies. Using multi-omics approaches incorporating bulk RNAseq, single nuclei RNAseq, spatial transcriptomics, small RNAseq, and mass spectrometry discovery proteomics, a putative mechanism connecting proximal tubule injury to alterations in sodium solute transporters and hypertension was established. The direct physiological interaction between Arhgef11 and Cgnl1 on hypertension and CKD is currently underway using a double knockout model (SS- Arhgef11 -/- Cgnl1 -/- ). In addition, to better elucidate the impact of loss of Arhgef11 , Cgnl1 , or both genes together, gene-edited cell lines using CRISPR technology has been generated and are also being studied. It is anticipated that completion of this work will lead to a better understanding of the role of genetics in hypertensive CKD, the influence of factors that complicate kidney disease, and potential new therapeutic targets.