Cyclo (His-Pro) is an effective treatment for the AKI-to-CKD Transition

Acute kidney injury (AKI) with maladaptive repair induces transition to chronic kidney disease (CKD) through inflammation, oxidative stress, and inappropriate homeostatic responses, including senescence and apoptosis. Here, we demonstrate that administration of cyclo Histidine-Proline (Cyclo His-Pro, CHP) protects against kidney injury and progression to CKD. Exogenous CHP pre-treatment preserved kidney function and produced significant reduction in tubular injury, apoptosis, and inflammatory cell infiltration in an ischemia-reperfusion injury (IRI) model. Compared with 5/6 nephrectomy (Nx) control rats, kidney function was protected and fibrosis was attenuated in CHP-treated 5/6 Nx rats. CHP also improved kidney injury in a unilateral ureteral obstruction (UUO) model with both prophylactic and therapeutic treatment regimens. To translate our observations to the human setting, we evaluated the relationship between endogenous CHP levels and CKD progression. As kidney function deteriorated, plasma CHP concentration increased, whereas tissue expression of Nrf2 displayed a negative relationship with CKD progression, suggesting that plasma CHP levels increase as a compensatory process to enhance the Nrf2 pathway activity. The data presented here support the efficacy of exogenous CHP treatment in preventing AKI-to-CKD transition potentially through Nrf2 pathway activation. Results: Cyclo (His-Pro) is an effective treatment for the AKI-to-CKD Transition Overall design: Design: The purpose of this study was to investigate the effect of CHP on renal protection and provide support for its potential therapeutic use in human kidney disease. IRI mice model that represented the AKI was used to examine the protective effect of CHP. Then, we tested microarray analysis with IRI mice kidneys, to identify the renal protection mechanisms of CHP at the transcriptomic level. We tested hypoxia-reoxygenation model and H2O2 oxidative stress induction model with primary cultured hTECs to evaluate the anti-oxidant, anti-inflammatory, and renoprotective effect of CHP in AKI in vitro model. Assessment was performed in UUO in vivo model to determine the inhibitory effect of CHP on AKI to CKD transition. Potential prophylactic and therapeutic effects of CHP was analyzed in UUO mice model. To evaluate the renoprotective effect of CHP on CKD, We used 5/6 Nx rat model. RNA sequencing using 5/6 nephrectomized rat kidneys was performed to study the effects at the molecular level. For in vitro experiments, primary cultured hTECs and podocytes were induced by various types of stress such as TGFß or H2O2 to assess the anti-apoptotic and anti-fibrotic effect of CHP treatment. The associations between endogenous CHP level and CKD progression in humans were assessed by measuring CHP concentration with plasma and urine samples derived from CKD patients. The study was not blinded.