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

Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury. Ischemia/reperfusion injury riggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes acute kidney injury and subsequent chronic kidney disease. 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. Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated acute kidney injury and subsequent chronic kidney disease, by comparing Ptprz knockout with wild-type mice after ischemia/reperfusion injury. Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after ischemia/reperfusion injury in mice. Using Ptprz knockout mice we determined that during acute kidney injury and chronic kidney disease kidney pathology, and loss of kidney function were ameliorated. Ptprz-dependent mechanisms mediated: (i) tubular epithelial cell expression of chemokines that fostered macrophage and T cell rich renal inflammation, and (ii) tubule injury and apoptosis, that resulted in the loss of tubules and interstitial fibrosis during chronic kidney disease . Mechanistically, Ptprz dependent tubule epithelial cells released mediators that:(i) promoted tubule cytotoxicity, and thereby, shortened tubule survival, and (ii) stimulated Ptprz expressing macrophages to generate mediators that induce kidney destruction. These findings are translational, as after ischemia reperfusion injury in human kidney transplants, 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. Conclusions: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote acute kidney injury and subsequent chronic kidney disease.