The struggle for energy in podocytes leads to nephrotic syndrome.

Podocytes are terminally differentiated post-mitotic cells similar to neurons, and their damage leads to nephrotic syndrome, which is characterized by massive proteinuria associated with generalized edema. A recent functional genetic approach has identified the pathological relevance of several mutated proteins in glomerular podocytes to the mechanism of proteinuria in hereditary nephrotic syndrome. In contrast, the pathophysiology of acquired primary nephrotic syndrome, including minimal change disease, is still largely unknown. We recently demonstrated the possible linkage of an energy-consuming process in glomerular podocytes to the mechanism of proteinuria. Puromycin aminonucleoside nephrosis, a rat model of minimal change disease, revealed the activation of the unfolded protein response (UPR) in glomerular podocytes to be a cause of proteinuria. The pretreatment of puromycin aminonucleoside rat podocytes and cultured podocytes with the mammalian target of rapamycin (mTOR) inhibitor everolimus further revealed that mTOR complex 1 consumed energy, which was followed by UPR activation. In this paper, we will review nutritional transporters to summarize the energy uptake process in podocytes and review the involvement of the UPR in the pathogenesis of glomerular diseases. We will also present additional data that reveal how mTOR complex 1 acts upstream of the UPR. Finally, we will discuss the potential significance of targeting the energy metabolism of podocytes to develop new therapeutic interventions for acquired nephrotic syndrome.