Ptprz Signaling, Tubule-Mediated and Macrophage-Mediated Kidney Injury, and Subsequent CKD.

Abstract

Ischemia/reperfusion injury induces Ptprz in mouse kidney tubules and macrophages. Stimulated tubules and macrophages expressing Ptprz promote kidney destruction. Ptprz is similarly expressed in inflamed mouse and human (transplant) kidneys, thus are translational. Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to AKI. Ischemia/reperfusion injury triggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes AKI and subsequent CKD. IL-34 engages the cognate receptor, c-FMS, expressed by macrophages, and the recently discovered protein-tyrosine phosphatase ζ (Ptprz). Ptprz binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after ischemia/reperfusion injury. We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated AKI and subsequent CKD by comparing <i>Ptprz</i> knockout with wild-type mice after ischemia/reperfusion injury. Ptprz was expressed by leukocytes and in tubular epithelial cells after ischemia/reperfusion injury in mice. Using <i>Ptprz</i> knockout mice, we determined that during AKI and CKD kidney pathology, loss of kidney function was ameliorated. Ptprz-dependent mechanisms mediated: (<i>1</i>) tubular epithelial cell expression of chemokines that fostered macrophage and T-cell–rich renal inflammation and (<i>2</i>) tubule injury and apoptosis, which resulted in the loss of tubules and interstitial fibrosis during CKD. Mechanistically, Ptprz-dependent tubule epithelial cells released mediators that (<i>1</i>) promoted tubule cytotoxicity and, thereby, shortened tubule survival and (<i>2</i>) stimulated Ptprz-expressing macrophages to generate mediators that induce kidney destruction. These findings are translational, as after ischemia-reperfusion injury in human kidney transplants, protein-tyrosine phosphasase zeta (PTPRZ) and PTPRZ ligands were upregulated and expressed by the same cell populations as in mice. Moreover, PTPRZ levels in sera were elevated in kidney transplant patients. Intrarenal Ptprz-dependent macrophage and tubular epithelial cell–mediated mechanisms promote AKI and subsequent CKD.