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Thiobarbiturate-Derived Compound MHY1025 Alleviates Renal Fibrosis by Modulating Oxidative Stress, Epithelial
Jeongwon Kim1, Jieun Lee2, Dahye Yoon2
1Department of Pharmacy, Research Institute for Drug Development, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
Abstract:
Chronic kidney disease (CKD) is a kidney structure and function abnormality. CKD development and progression are strongly influenced by oxidative stress and inflammatory responses, which can lead to tubulointerstitial fibrosis. Unfortunately, there are no effective or specific treatments for CKD. We investigated the potential of the thiobarbiturate-derived compound MHY1025 to alleviate CKD by reducing oxidative stress and inflammatory responses. In vitro experiments using NRK52E renal tubular epithelial cells revealed that MHY1025 significantly reduced LPS-induced oxidative stress and inhibited the activation of the NF-κB pathway, which is involved in inflammatory responses. Furthermore, treatment with MHY1025 significantly suppressed the expression of fibrosis-related genes and proteins induced by TGFβ in NRK49F fibroblasts. Furthermore, we analyzed the MHY1025 effects in vivo. To induce kidney fibrosis, mice were administered 250 mg/kg folic acid (FA) and orally treated with MHY1025 (0.5 mg/kg/day) for one week. MHY1025 effectively decreased the FA-induced inflammatory response in the kidneys. The group treated with MHY1025 exhibited a significant reduction in cytokine and chemokine expression and decreased immune cell marker expression. Decreased inflammatory response was associated with decreased tubulointerstitial fibrosis. Overall, MHY1025 alleviated renal fibrosis by directly modulating renal epithelial inflammation and fibroblast activation, suggesting that MHY1025 has the potential to be a therapeutic agent for CKD.
Insights
MHY1025, a novel compound, effectively reduces oxidative stress and inflammation, key drivers of chronic kidney disease (CKD). This compound alleviates renal fibrosis in preclinical models, showing promise as a potential therapeutic agent for CKD.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) is characterized by kidney damage and impaired function.
- Oxidative stress and inflammation are primary contributors to CKD progression and tubulointerstitial fibrosis.
- Current CKD treatments lack specificity and efficacy.
Purpose of the Study:
- To evaluate the therapeutic potential of MHY1025 in mitigating CKD.
- To investigate MHY1025's ability to reduce oxidative stress and inflammation in kidney disease models.
Main Methods:
- In vitro studies utilized NRK52E renal tubular epithelial cells and NRK49F fibroblasts to assess MHY1025's effects on oxidative stress, NF-κB pathway activation, and TGFβ-induced fibrosis.
- In vivo experiments involved folic acid-induced kidney fibrosis in mice, with MHY1025 administered orally to assess its impact on inflammation and fibrosis.
Main Results:
- MHY1025 significantly reduced lipopolysaccharide-induced oxidative stress and NF-κB pathway activation in renal tubular cells.
- MHY1025 suppressed TGFβ-induced expression of fibrosis-related genes and proteins in fibroblasts.
- In vivo, MHY1025 decreased folic acid-induced kidney inflammation, cytokine/chemokine expression, and immune cell markers, leading to reduced tubulointerstitial fibrosis.
Conclusions:
- MHY1025 demonstrates efficacy in alleviating renal fibrosis by modulating renal epithelial inflammation and fibroblast activation.
- MHY1025 exhibits potential as a novel therapeutic agent for treating chronic kidney disease.
