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A Cyclopentanone Compound Attenuates the Over-Accumulation of Extracellular Matrix and Fibrosis in Diabetic
Chunyin Tang1, Meng Wang1, Jieting Liu1
1College of Life Science, Mudanjiang Medical University, Mudanjiang 157011, China.
Abstract:
Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound H8 alleviated ECM over-deposition and fibrosis to prevent and treat diabetic nephropathy. HK-2 cell viability after treatment with H8 was measured by an MTT assay. ECM alterations and renal fibrosis were identified in vitro and in vivo. A pharmacological antagonist was used to detect associations between H8 and the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. H8 binding was identified through computer simulation methods. Studies conducted on high glucose and transforming growth factor β1 (TGF-β1)-stimulated HK-2 cells revealed that the p38MAPK inhibitor SB 202190 and H8 had similar pharmacological effects. In addition, excessive ECM accumulation and fibrosis in diabetic nephropathy were remarkably improved after H8 administration in vivo and in vitro. Finally, the two molecular docking models further proved that H8 is a specific p38MAPK inhibitor that forms a hydrogen bond with the LYS-53 residue of p38MAPK. The cyclopentanone compound H8 alleviated the over-deposition of ECM and the development of fibrosis in diabetic nephropathy by suppressing the TGF-β/p38MAPK axis.
Insights
Cyclopentanone compound H8 reduces extracellular matrix (ECM) over-deposition and fibrosis in diabetic nephropathy. This compound acts as a p38 mitogen-activated protein kinase (p38MAPK) inhibitor, offering a potential therapeutic strategy for kidney disease.
Area of Science:
- Nephrology
- Biochemistry
- Pharmacology
Background:
- Excessive extracellular matrix (ECM) deposition drives chronic kidney diseases like diabetic nephropathy.
- Mechanisms to reduce ECM deposition in diabetic nephropathy are not fully understood.
- Targeting ECM accumulation is crucial for preventing and treating kidney fibrosis.
Purpose of the Study:
- To investigate the efficacy of cyclopentanone compound H8 in alleviating ECM over-deposition and fibrosis in diabetic nephropathy.
- To determine if H8 targets the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway.
- To explore H8 as a potential therapeutic agent for diabetic nephropathy.
Main Methods:
- In vitro studies using HK-2 cells stimulated with high glucose and TGF-β1.
- In vivo assessment of ECM alterations and renal fibrosis in a diabetic nephropathy model.
- MTT assay for cell viability.
- Pharmacological inhibition and molecular docking to identify the target pathway (p38MAPK).
Main Results:
- H8 demonstrated similar effects to the p38MAPK inhibitor SB 202190 in HK-2 cells.
- H8 significantly improved ECM accumulation and fibrosis both in vitro and in vivo.
- Molecular docking confirmed H8 as a specific p38MAPK inhibitor, binding to LYS-53 via a hydrogen bond.
Conclusions:
- Cyclopentanone compound H8 effectively alleviates ECM over-deposition and fibrosis in diabetic nephropathy.
- H8 functions by suppressing the TGF-β/p38MAPK signaling axis.
- H8 represents a promising therapeutic candidate for managing diabetic nephropathy and associated renal fibrosis.
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