*Purpose: Cyclic(His-Pro) (CHP) is an endogenous cyclic dipeptide that has antioxidative, anti-inflammatory effect via Nuclear factor erythroid 2-related factor (Nrf2) pathway. Endogenous CHP is distributed in the central nervous system (CNS), gastrointestinal tract, blood, semen and prostate in humans. The purpose of study is to identify the relationship between endogenous CHP levels and chronic kidney disease, and to investigate the effect of exogenous CHP therapy on kidney disease models.

*Methods: In this study, we analyzed plasma samples of patients who were diagnosed chronic kidney disease. Plasma CHP concentrations were measured by using liquid chromatography with mass spectrometry/mass spectrometry (LC-MS/MS). Analyses were performed to access the relationship between CHP concentration and pathologic, functional markers of kidney disease. To investigate the effect of exogenous CHP on kidney injury, we used ischemia-reperfusion-injury mice model, 5/6 nephrectomy rat model for in vivo study. And for in vitro study, we used TGF beta or hypoxia induced injury model that using primary cultured human kidney cell.

*Results: Plasma CHP level was correlated with CKD progression. Exogenous CHP pre-treatment prevented kidney function and accompanied by a significant reduction in ischemia-induced tubular injury, apoptosis, and inflammatory cell infiltration on renal IRI model. In vitro stimulation of TECs with hypoxia, CHP-mediated renal protection was associated with reduced IL-11, IL-18, reactive oxygen species (ROS) and the proportion of dead cells. Compared with control-treated 5/6 Nx rat, CHP-treated 5/6 Nx rat also restored kidney function and decreased proteinuria and pathologically decreased glomerulosclerosis, tubule-interstitial fibrosis in the remnant kidney of 5/6 nephrectomized rat. The administration of exogenous CHP significantly reduced not only ROS production via Nrf2-dependent pathway, but also the resultant apoptosis induced by H₂O₂ in cultured human podocytes. Microarray analysis highlights a cascade of specific gene expression patterns related to kidney injury, repair, and innate immunity. Notably, tubular epithelial cell and podocytes cell cycle arrest in G2/M mediates oxidative stress after injury.

*Conclusions: Endogenous concentration of CHP reflects the kidney function and pathologic findings. This study has uncovered a major protective role of exogenous CHP in IRI and 5/6 nephrectomy through TECs and podocytes regeneration that could be potentiated as a therapeutic strategy.

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