The targeted podocyte

Abstract

The podocyte plays a key role both in maintenance of the glomerular filtration barrier and in glomerular structural integrity. Podocyte injury and loss contribute to proteinuria and progressive sclerosis. Inhibitors of mammalian target of rapamycin (mTOR) have variably decreased or caused proteinuria and sclerosis in human disease and experimental settings. In this issue of the JCI, two interesting studies of podocyte-specific manipulation of the mTOR system shed light on the complexity of this pathway in the podocyte.

Figure 1. Glomerular parietal epithelial cells and the injury response.

(A) The glomerular tuft is surrounded by Bowman’s capsule, which is lined by parietal epithelial cells. The highly specialized podocyte covers the glomerular capillary tuft and is key for maintaining glomerular structure and permeability barrier function. Podocytes have limited proliferative capacity. (B) After podocyte injury and detachment, parietal epithelial cells may migrate along Bowman’s capsule and transition to the tuft to areas of injury. Whether these parietal cells are reparative or ultimately promote sclerosis after injury remains unknown.

Figure 2. Podocyte maintenance is dependent on a fine-tuned balance of mTORC1 and mTORC2 activity.

mTORC1 signaling is normally activated by nutrients such as amino acids and growth factors. The primary signals for mTORC2 activation are unknown. Activation of mTORC1, as occurs in diabetic nephropathy, results in effaced foot processes and proteinuria and also is associated with mesangial expansion. mTORC1 activation may also result in transition of the podocyte to a more mesenchymal phenotype, resulting in loss of adhesion to the underlying GBM and detachment, further promoting proteinuria and ultimately sclerosis. Rapamycin has an immediate inhibitory effect on mTORC1 and with chronic use may also, through unknown mechanisms, inhibit mTORC2. Inhibition of mTORC1, especially during development or other physiologic or pathophysiologic growth, may also cause podocyte injury (8, 9). Added inhibition of mTORC2 activation causes more severe podocyte injury, sclerosis, and proteinuria (8), illustrating the dependence of normal podocyte function and structure on balance of the two complexes.