Involvement of the IP3R-Grp75-VDAC1-MCU calcium axis in proteinuria in adriamycin-induced nephropathy rats

Abstract Background: Podocyte injury plays a key role in the development of proteinuria. We previously found that the intracellular inositol 1, 4, 5-trisphosphate receptor (IP3R)- glucose-regulated protein 75 (Grp75)- voltage dependent anion channel 1 (VDAC1)- mitochondrial calcium uniporter (MCU) calcium axis contributes to podocyte injury in cultured mouse podocytes. This study investigated whether the IP3R-Grp75-VDAC1-MCU calcium axis is involved in the development and improvement of proteinuria in nephropathy rats. Methods: The expression of members of the IP3R-Grp75-VDAC1-MCU calcium axis in the renal cortex of a previously established adriamycin (ADR)-induced nephropathy rat model and cultured mouse podocytes was investigated by western blot analysis and immunohistochemical staining. The effects of ruthenium red (RR), an MCU inhibitor, on interactions in the IP3R-Grp75-VDAC1-MCU calcium axis were investigated by in vitro co-immunoprecipitation assays. Results: In adriamycin induced nephropathy rat, the expression of members of the glomerular IP3R-Grp75-VDAC1-MCU calcium axis increased significantly compared with the normal control rats. RR inhibited the upregulation of members of the IP3R-Grp75-VDAC1-MCU calcium axis induced by ADR and their interactions. Conclusion: The IP3R-Grp75-VDAC1-MCU calcium axis is involved in proteinuria in ADR-induced nephropathy and can be inhibited by RR.