Mitochondrial Damage Induced by Excess Growth Hormone in Glomerular Podocytes: Implications in Diabetic Nephropathy

*Corresponding author: (e-mail: [e-mail]).

Abstract

Background: Podocyte injury contributes to proteinuria and implicates in the pathology of diabetic nephropathy. Mitochondrial damage, decreased ATP, increased ROS levels are associated with kidney injury. Although high growth hormone (GH) in diabetes implicates ROS-induced podocyte damage and proteinuria, the precise role of GH on podocyte mitochondrial function remained unexplored.

Methods: In this study, we investigated the role of GH on podocyte morphology and function in vivo and in vitro models of podocytes using confocal microscopy, TEM imaging, immunoblotting, and qRT-PCR. Mitophagy reporter plasmid transfection was also performed. Calcium influx assay and metabolic flux analysis were done in vitro.

Results: Podocytes exposed to GH were shown to have enhanced intracellular calcium influx, preferably via elevated expression of TRPC6. Excess intracellular calcium in GH-treated podocytes was paralleled with altered mitochondrial fission–fusion dynamics and an increase in mitophagy markers; PINK1, Parkin, and LC3 expression. Extensive perinuclear localization of mitochondria in GH-treated podocytes was observed. Functional analysis revealed decreased mitochondrial and glycolytic ATP-production rates in GH-treated podocytes. Interestingly, TEM analysis of podocytes from GH-treated mice kidney sections revealed irregularities in the localization and morphology of podocyte mitochondria.

Conclusion: GH induced excess calcium into podocytes via TRPC6. Excess calcium potentially causes mitochondrial damage in both cultured and mouse podocytes and could contribute significantly to podocyte injury and implicate the progression of DN. Therapeutic targets to ameliorate mitochondrial damage could prevent DN in diabetics.

Publication History

Article published online:
08 July 2024