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Ptprz Signaling, Tubule and Macrophage-Mediated Renal Injury and Subsequent Chronic Kidney Disease [TECs]

ABSTRACT: Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury (AKI). Ischemia/reperfusion injury (I/R) 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 Z (Ptprz). Ptprz, binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after I/R. Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated AKI and subsequent CKD, by comparing Ptprz knockout (KO) with wild-type (WT) mice after I/R. Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after I/R in mice. Using Ptprz KO mice we determined that during AKI and CKD renal pathology, and loss of renal 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 CKD. As macrophages release mediators that induce tubular epithelial cell apoptosis, thus Ptprz-dependent mechanisms promote tubule damage. These findings are translational, as after I/R 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. Conclusion: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote AKI and subsequent CKD.

ORGANISM(S): Mus musculus

PROVIDER: GSE284134 | GEO | 2025/07/02

REPOSITORIES: GEO

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Project description:Renal gluconeogenesis accounts for half of systemic gluconeogenesis during starvation, but its regulatory mechanisms and implications in chronic kidney disease (CKD) remain unknown. In this study, using single-cell RNA sequencing of starved kidneys and various animal models, we aimed to identify key pathways involved in renal gluconeogenesis and their role in the development of hypoglycemia during starvation in diseased kidneys. Under the starvation condition, renal gluconeogenesis was highly induced in proximal tubule cells with FOXO1 activation. In renal tubular epithelial cells, starvation-induced FOXO1 activation was required to stimulate gluconeogenesis and promote glucose production. We further analyzed whether renal FOXO1-mediated gluconeogenesis is impaired in CKD. In CKD animal models, the kidneys exhibited reduced FOXO1 and gluconeogenic protein expression; however, serum glucose levels remained unchanged, suggesting that diminished renal gluconeogenesis does not significantly impact circulating glucose levels. When CKD mice were subjected to starvation, serum glucose levels were significantly reduced after 72 hours. In the CKD model, FOXO1 activation failed, accompanied by a lower induction of gluconeogenic protein expression. Similar to diseased condition, aged mice exposed to starvation also showed impaired gluconeogenic response in the kidney, contributing to reduced circulating glucose levels. Under the in vitro condition, we found that profibrotic TGFβ1 inhibits starvation-induced gluconeogenesis by directly suppressing the FOXO1 signaling pathway in tubular cells. Finally, we generated tubule-specific FOXO1 knockout (KO) mice by crossing FOXO1 floxed mice with Ksp-cre mice. These tubule-specific FOXO1 KO mice exhibited reduced expression of gluconeogenic genes in the kidney, leading to hypoglycemia during starvation. Collectively, we demonstrated crucial role of renal FOXO1 in gluconeogenesis during starvation, and its implication in kidney disease.

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Ptprz Signaling, Tubule and Macrophage-Mediated Renal Injury and Subsequent Chronic Kidney Disease [TECs]

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