A reciprocal regulation of spermidine and autophagy in podocytes maintains the filtration barrier

Kidney Int. 2020 Dec;98(6):1434-1448. doi: 10.1016/j.kint.2020.06.016. Epub 2020 Jun 27.


Podocyte maintenance and stress resistance are exquisitely based on high basal rates of autophagy making these cells a unique model to unravel mechanisms of autophagy regulation. Polyamines have key cellular functions such as proliferation, nucleic acid biosynthesis and autophagy. Here we test whether endogenous spermidine signaling is a driver of basal and dynamic autophagy in podocytes by using genetic and pharmacologic approaches to interfere with different steps of polyamine metabolism. Translational studies revealed altered spermidine signaling in focal segmental glomerulosclerosis in vivo and in vitro. Exogenous spermidine supplementation emerged as new treatment strategy by successfully activating autophagy in vivo via inhibition of EP300, a protein with an essential role in controlling cell growth, cell division and prompting cells to differentiate to take on specialized functions. Surprisingly, gas chromatography-mass spectroscopy based untargeted metabolomics of wild type and autophagy deficient primary podocytes revealed a positive feedback mechanism whereby autophagy itself maintains polyamine metabolism and spermidine synthesis. The transcription factor MAFB acted as an upstream regulator of polyamine metabolism. Thus, our data highlight a novel positive feedback loop of autophagy and spermidine signaling allowing maintenance of high basal levels of autophagy as a key mechanism to sustain the filtration barrier. Hence, spermidine supplementation may emerge as a new therapeutic to restore autophagy in glomerular disease.

Keywords: LC3; MAFB; autophagy; podocyte; polyamine; spermidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • Cell Proliferation
  • Glomerulosclerosis, Focal Segmental*
  • Humans
  • Podocytes*
  • Spermidine* / metabolism


  • Spermidine