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IP3R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in
1Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
BMC Nephrology
|June 17, 2018
Summary
This study reveals a new pathway where the inositol 1,4,5-triphosphate receptor (IP3R)/Grp75/VDAC1/MCU axis drives podocyte apoptosis via mitochondrial calcium overload. Inhibiting this axis shows promise for protecting podocytes.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Medicine
Background:
- The precise mechanisms of podocyte apoptosis remain incompletely understood.
- The role of the endoplasmic reticulum (ER)-mitochondria calcium regulation axis (IP3R/Grp75/VDAC1/MCU) in podocyte apoptosis is unclear.
- This study investigates this axis's involvement in podocyte apoptosis and potential therapeutic targets.
Purpose of the Study:
- To elucidate the role of the IP3R-Grp75-VDAC1-MCU calcium axis in podocyte apoptosis.
- To explore the potential of targeting this axis for podocyte protection.
Main Methods:
- Analyzed expression of IP3R, Grp75, VDAC1, and MCU, and mitochondrial Ca2+ in cultured mouse podocytes undergoing apoptosis induced by Adriamycin or angiotensin II.
- Investigated protein interactions within the IP3R-Grp75-VDAC1 complex using co-immunoprecipitation.
- Assessed the effects of agonists and antagonists of the axis on mitochondrial Ca2+ and apoptosis, and evaluated an MCU inhibitor in a rat model of nephropathy.
Main Results:
- Increased expression of IP3R, Grp75, VDAC1, and MCU, along with enhanced IP3R-Grp75-VDAC1 complex interaction, mitochondrial Ca2+ overload, and caspase-3 activation were observed during podocyte apoptosis.
- Agonists of the axis exacerbated mitochondrial Ca2+ overload and apoptosis, while antagonists prevented these effects.
- An MCU inhibitor reduced proteinuria and podocyte damage in rats with Adriamycin-induced nephropathy.
Conclusions:
- The IP3R-Grp75-VDAC1-MCU calcium axis mediates podocyte apoptosis by promoting mitochondrial Ca2+ overload.
- Inhibitors targeting Ca2+ transfer from ER to mitochondria demonstrate protective effects on podocytes.
- Antagonists of this axis represent promising novel therapeutic agents for podocyte protection and treating kidney diseases.
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