Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

Abstract

Mitochondrial function is essential for bioenergetics, metabolism, and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity, and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. In this study, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury, and glomerular pathology. RNA sequencing revealed that mGPDH regulated the receptor for the advanced glycation end product (RAGE) signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased reactive oxygen species generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

Effects of Self-Made Prescription Compound Rhodiola on the Ultrastructure of Podocytes in Rats with Type 2 Diabetic Nephropathy

“…Studies have shown that podocyte injury plays a key role in the pathogenesis of DN [ 9 , 10 ]. The number and density of podocytes in the early stage of DN have begun to decrease and worsen with the aggravation of the disease [ 11 ]. The density and total number of podocytes are reduced by apoptosis and shedding due to injury, and the residual podocyte widens and fuses, resulting in compensatory hypertrophy, leading to glomerular sclerosis and destruction of the glomerular filtration barrier [ 12 ].…”

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

“…A secreted glycoprotein, progranulin, can activate SIRT1/PGC-1α/FOXO1 signaling in podocytes exposed to HG, which protected against podocyte injury in mice with DN ( 62 ). Recent finding emphasized the importance of mitochondrial glycerol 3-phosphate dehydrogenase in inducing mitochondrial biogenesis in podocytes, which protected the cells against hyperglycemia-induced impairment of mitochondrial bioenergetics and increased ROS production ( 63 ).…”

Mechanisms of podocyte injury and implications for diabetic nephropathy

“…Accumulation of mtROS has been shown in various CKD, including DN and FSGS, and enhanced mtROS production recently confirmed in diabetic db/db mice by real-time mitochondrial redox assessment [ 90 ]. Moreover, podocyte-specific overexpression of the antioxidant metallothionein ameliorates experimental DN [ 91 ], while podocyte-restricted deletion of mitochondrial glycerol 3-phosphate dehydrogenase exacerbates mitochondrial oxidative stress, podocyte loss, and proteinuria in animal models of both DN and FSGS [ 92 ]. However, most of the studies did not identify the glomerular cell type in which mtROS exert their deleterious effect [ 93–95 ].…”