The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin–mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation–related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis — all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.
Victor G. Puelles, James W. van der Wolde, Nicola Wanner, Markus W. Scheppach, Luise A. Cullen-McEwen, Tillmann Bork, Maja T. Lindenmeyer, Lukas Gernhold, Milagros N. Wong, Fabian Braun, Clemens D. Cohen, Michelle M. Kett, Christoph Kuppe, Rafael Kramann, Turgay Saritas, Claudia R. van Roeyen, Marcus J. Moeller, Leon Tribolet, Richard Rebello, Yu B.Y. Sun, Jinhua Li, Gerhard Müller-Newen, Michael D. Hughson, Wendy E. Hoy, Fermin Person, Thorsten Wiech, Sharon D. Ricardo, Peter G. Kerr, Kate M. Denton, Luc Furic, Tobias B. Huber, David J. Nikolic-Paterson, John F. Bertram