Cyclo (His-Pro) is an effective treatment for the AKI-to-CKD Transition
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ABSTRACT:
PROVIDER: PRJNA668105 | ENA |
REPOSITORIES: ENA
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Project description: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
2025-02-08 | GSE159228 | GEO
Project description:Macrophages are key immune cells in AKI and may determine the fate of AKI to CKD progression. Here, by taking advantages of single cell RNA-sequencing technology, we generated a mononuclear macrophage atlas from the initiation of AKI till the progression to CKD.
2024-12-31 | GSE239287 | GEO
Project description:Kidneys have a limited ability to self-repair, and their response to injury not seldomly leads to chronic kidney disease (CKD). An intriguing phenomenon of successful recovery is observed in models of unilateral acute kidney injury (AKI) upon contralateral nephrectomy. Here we aimed to better understand the cellular mechanisms of this enhanced reparative effect.In a time-course study with different nephrectomy delay times, we found that the most effective rescue after injury was observed when contralateral nephrectomy was performed early during AKI in both rats and mice. This timely intervention led to full functional recovery and attenuation of tubular atrophy, fibrosis, and inflammation, averting AKI-to-CKD transition. Morphometry of histopathology using pathomics revealed distinct trajectories of structural alterations of kidney tubules, distinguishing between atrophy and repair, as adaptive signatures. These responses were corroborated by transcriptomics analysis, which indicated improved cellular energy metabolism after nephrectomy. Lineage tracing of tubular progenitor cells showed that nephrectomy robustly stimulated their clonal expansion, surpassing the levels observed during spontaneous self-repair. Live cell cycle/DNA-content analysis of tubular cells demonstrated a robust polyploid response immediately after the ischemic insult, and revealed that nephrectomy attenuated long term tubular cell polyploidization, a contributor to CKD. Altogether, our data revealed that early timing of nephrectomy in experimental AKI induces an efficient repair response, involving tubular epithelial regeneration while counteracting the progression towards CKD.
2024-12-31 | GSE268009 | GEO
Project description:Cyclo(His-Pro): A further step in the management of steatohepatitis
| PRJNA826474 | ENA
Project description:Cyclo (His-Pro): a further step in the prevention of steatohepatitis
| PRJNA962499 | ENA
Project description:Cyclo(His-Pro): A further step in the management of steatohepatitis
| PRJNA893223 | ENA
Project description:Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the world, and despite this has no approved therapy. The naturally occurring compound Cyclo (His-Pro) (CHP) has been described as having anti-inflammatory and hypoglycemic properties. We show that CHP administration in a mouse model of NAFLD/NASH protects against disease progression. Based on our study, CHP prevents overall lipid accumulation, reducing body weight and fat mass. The treatment lowers systemic inflammation and prevents the development of insulin resistance. Specifically, the effect of CHP in the liver is remarkable, it reduces the steatosis while preventing inflammation and fibrosis, typical features of NADLF/NASH progression. The analysis of the liver transcriptome underscores the anti-fibrotic and anti-inflammatory effects of the treatment, supported by histology results. CHP, which has an excellent safety record, may hence represent a novel approach to manage NAFLD.
2023-08-14 | GSE230745 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the world, and despite this has no approved therapy. The naturally occurring compound Cyclo (His-Pro) (CHP) has been described as having anti-inflammatory and hypoglycemic properties. We show that CHP administration in a mouse model of NAFLD/NASH protects against disease progression. Based on our study, CHP prevents overall lipid accumulation, reducing body weight and fat mass. The treatment lowers systemic inflammation and prevents the development of insulin resistance. Specifically, the effect of CHP in the liver is remarkable, it reduces the steatosis while preventing inflammation and fibrosis, typical features of NADLF/NASH progression. The analysis of the liver transcriptome underscores the anti-fibrotic and anti-inflammatory effects of the treatment, supported by histology results. CHP, which has an excellent safety record, may hence represent a novel approach to manage NAFLD.
2023-08-14 | GSE200750 | GEO
Project description:Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-β suppressed TNF-α- and IL-1β-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.
2024-09-03 | GSE254359 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is now considered the most common liver disease in the world, yet no pharmacological treatment has been approved. The naturally occurring compound Cyclo (His-Pro) (CHP) appears as an interesting candidate for the management of NAFLD, given its safety records and its anti-inflammatory effect. We show here that CHP administration protects against progression towards steatohepatitis (NASH) and fibrosis in two different mouse models of liver injury: a model of dietary NAFLD/NASH, achieved with thermoneutral housing in combination with a western diet, and a model of liver fibrosis by repeated injections with carbon tetrachloride. CHP administration prevents overall lipid accumulation, reducing body weight and fat mass. Treated animals show lower systemic inflammation and improved glycemia. Histo-pathology and liver transcriptomics highlight reduced steatosis upon CHP, together with lower inflammation and fibrosis, which are typical features of NAFLD progression. For the first time, we identified ERK as an early mediator of CHP response, although more work is required to elucidate its precise mechanism of action. In conclusion, our work indicates that CHP is a novel and efficacious strategy to manage NAFLD, fuelling optimism for potential clinical studies.
2023-08-14 | GSE216366 | GEO