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Tissue kallkreins protect mice against anti‐GBM induced nephritis and are potential Sle3 candidate genes

B6.Sle3 congenic mice, bearing NZM2410 derived Sle3 lupus susceptibility loci on chromosome 7, suffer severe anti‐GBM nephritis compared to B6, upon experimental insult with anti‐GBM antibodies. The expression and activity of tissue kallikreins were significantly increased in the kidney cortex of B6, but not in B6.Sle3 mice (2 fold, p<0.001), post anti‐GBM challenge. Klks act predominantly through the generation of bradykinin, which then binds to kinin B2 receptor. Blocking of the B2 receptor using antagonist HOE140 precipitated severe nephritis in B6 mice with a 3.5‐fold increase in proteinuria and a 2‐fold increase in BUN (p < 0.001). On the other hand, delivering klk1 gene into B6.Sle3 mice via adenovirus ameliorated anti‐GBM induced nephritis in these mice. Several polymorphic residues have been identified in the promoters of the differentially expressed klk genes. Given that the klk genes are clustered together within the Sle3 lupus nephritis susceptibility interval on chromosome 7, these studies indicate that klks play important protective role in immune nephritis, and the promoter polymorphisms in klk genes could constitute potential candidate genes for anti‐GBM and lupus nephritis.