Mitochondrial function is
essential for bioenergetics, metabolism and signaling and is compromised in
diseases such as proteinuric kidney diseases, <a>contributing</a>
to the global burden of kidney failure, cardiovascular morbidity and death. The
key cell <a>type</a> that prevents proteinuria is the
terminally differentiated glomerular podocyte. Here, we <a>characterized</a>
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 <a>diabetes-</a> or adriamycin-induced
proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed
that mGPDH regulated the RAGE signaling
pathway, and inhibition of RAGE or its ligand, S100A10, protected against the
impaired mitochondrial bioenergetics and increased ROS
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 <a>significantly improved</a> 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.
Suppressed ER‐associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease
