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Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic
Minmin Gong1, Yujin Guo1, Hui Dong1
1Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background:
Mitochondrial dysfunction is implicated in the progression of diabetic kidney disease (DKD). Damaged mitochondria produce excessive reactive oxygen species (ROS) that can cause apoptosis. Mitochondrial dynamics control the quality and function of mitochondria. Targeting mitochondrial dynamics may reduce ROS-induced apoptosis and improve renal injury in DKD. Modified Hu-lu-ba-wan (MHLBW) shows distinct clinical effects on DKD patients, which are related to its role in antioxidant stress modulation. However, the relevant mechanisms of MHLBW have not been clearly explored.
Purpose:
This study was aimed to evaluate the therapeutic effects of MHLBW on spontaneous DKD mice and clarify the potential mechanisms.
Methods:
The main components of MHLBW were identified by HPLC. Using db/db mice as DKD models, we evaluated the therapeutic effects of MHLBW on mice after an 8-week administration. We investigated the molecular mechanism of MHLBW in regulating mitochondrial dynamic homeostasis, podocyte apoptosis, and glomerular damage. After that, computational docking analysis and in vitro experiments were conducted for further mechanism verification.
Results:
Intragastric administration of MHLBW for 8 weeks in db/db mice significantly improved glucose metabolism, basement membrane thickening, mesangial expansion, glomerular fibrosis, and podocyte injury. MHLBW can reverse podocyte apoptosis via promoting mitochondrial dynamic homeostasis, which was related to regulating the PKM2/ PGC-1α/Opa1 pathway. Berberine (BBR), one of the components of MHLBW, exhibited preeminent affinity with PKM2 as reflected by computational docking analysis. In cultured podocytes, BBR can also prevent apoptosis by promoting PKM2-mediated mitochondrial dynamic homeostasis.
Conclusion:
Our study demonstrates that MHLBW can treat DKD by inhibiting glomerular damage and podocyte apoptosis through positive regulation of PKM2-mediated mitochondrial dynamic homeostasis. These results may provide a potential strategy against DKD.
Insights
Modified Hu-lu-ba-wan (MHLBW) protects against diabetic kidney disease (DKD) by improving mitochondrial function and reducing podocyte apoptosis. This traditional herbal formula offers a potential therapeutic strategy for DKD.
Area of Science:
- Nephrology and Pharmacology
- Mitochondrial Biology and Oxidative Stress
Background:
- Mitochondrial dysfunction and excessive reactive oxygen species (ROS) contribute to diabetic kidney disease (DKD) progression and podocyte apoptosis.
- Mitochondrial dynamics are crucial for maintaining mitochondrial quality and function, presenting a potential therapeutic target for DKD.
- Modified Hu-lu-ba-wan (MHLBW) demonstrates clinical efficacy in DKD, likely through antioxidant mechanisms, but its precise molecular pathways remain unclear.
Purpose of the Study:
- To evaluate the therapeutic effects of MHLBW on spontaneous DKD in a mouse model.
- To elucidate the underlying molecular mechanisms by which MHLBW ameliorates DKD pathology.
Main Methods:
- High-performance liquid chromatography (HPLC) identified MHLBW components.
- Therapeutic effects were assessed in db/db mice over 8 weeks, focusing on mitochondrial dynamics, podocyte apoptosis, and glomerular damage.
- Computational docking and in vitro experiments verified molecular mechanisms, including the PKM2/PGC-1α/Opa1 pathway.
Main Results:
- MHLBW treatment significantly improved glucose metabolism and ameliorated kidney damage, including basement membrane thickening, mesangial expansion, fibrosis, and podocyte injury in db/db mice.
- MHLBW reversed podocyte apoptosis by promoting mitochondrial dynamic homeostasis via the PKM2/PGC-1α/Opa1 pathway.
- Berberine (BBR), a key MHLBW component, showed high affinity for PKM2 and protected cultured podocytes from apoptosis by enhancing PKM2-mediated mitochondrial dynamics.
Conclusions:
- MHLBW effectively treats DKD by inhibiting glomerular damage and podocyte apoptosis through the positive regulation of PKM2-mediated mitochondrial dynamic homeostasis.
- These findings suggest MHLBW as a promising therapeutic strategy for managing diabetic kidney disease.
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