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Lipid biology of the podocyte—new perspectives offer new opportunities

Nature Reviews Nephrology volume 10, pages 379–388 (2014)Cite this article

Subjects

Key Points

  • Lipids and lipid-related enzymes might modulate podocyte function

  • Lipid biology is important in understanding the pathogenesis of glomerular diseases of metabolic and nonmetabolic origin

  • Plasma membrane and intracellular lipids can modulate podocyte function irrespective of circulating lipids

  • Therapeutic strategies that target cellular lipids, such as cholesterol and sphingolipids, might be protective in kidney disease

Abstract

In the past 15 years, major advances have been made in understanding the role of lipids in podocyte biology. First, susceptibility to focal segmental glomerulosclerosis (FSGS) and glomerular disease is associated with an APOL1 sequence variant, is expressed in podocytes and encodes apolipoprotein L1, an important component of HDL. Second, acid sphingomyelinase-like phosphodiesterase 3b encoded by SMPDL3b has a role in the conversion of sphingomyelin to ceramide and its levels are reduced in renal biopsy samples from patients with recurrent FSGS. Furthermore, decreased SMPDL3b expression is associated with increased susceptibility of podocytes to injury after exposure to sera from these patients. Third, in many individuals with membranous nephropathy, autoantibodies against the phospholipase A2 (PLA2) receptor, which is expressed in podocytes, have been identified. Whether these autoantibodies affect the activity of PLA2, which liberates arachidonic acid from glycerophospholipids and modulates podocyte function, is unknown. Fourth, clinical and experimental evidence support a role for ATP-binding cassette sub-family A member 1-dependent cholesterol efflux, free fatty acids and glycerophospolipids in the pathogenesis of diabetic kidney disease. An improved understanding of lipid biology in podocytes might provide insights to develop therapeutic targets for primary and secondary glomerulopathies.

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Figure 1: Lipids in the slit diaphragm.
Figure 2: Podocyte handling of cholesterol and free fatty acids.
Figure 3: Role of lipids other than cholesterol in podocytes.

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Acknowledgements

A.F. and S.M. are supported by the NIH and NIDDK (grant numbers DK090316 and 5U24DX076169), the National Center for Advancing Translational Sciences (grant number 1UL1TR000460), the Diabetes Research Institute Foundation, the Nephcure Foundation and the Peggy and Harold Katz Family Foundation. S.M. is supported by the Stanley J. Glaser Foundation Research Award. J.B.K. is supported by the NIDDK Intramural Research Program.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, 1580 North West 10th Avenue, Miami, 33136, FL, USA

    Alessia Fornoni & Sandra Merscher

  2. Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, 10 Center Drive, 3N116, Bethesda, 20892-1268, MD, USA

    Jeffrey B. Kopp

Authors
  1. Alessia Fornoni
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Contributions

J.B.K. researched the data and A.F. wrote the article. S.M. and J.B.K. provided substantial contributions to discussion of the content and reviewed or edited the manuscript before submission.

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Correspondence to Alessia Fornoni.

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Competing interests

S.M. and A.F. hold patent application numbers US13/879,892, PCT/US11/56272: 'Assays, methods and kits for predicting renal disease and personalized treatment strategies'; PCT/US2012/062594, 'Soluble urokinase receptor (suPAR) in diabetic kidney disease'; PCT/US13/36484, 'Method of using cyclodextrin'. A.F. is a consultant for Hoffman-La Roche and Mesoblast. J.B.K. Declares no competing interests.

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Fornoni, A., Merscher, S. & Kopp, J. Lipid biology of the podocyte—new perspectives offer new opportunities. Nat Rev Nephrol 10, 379–388 (2014). https://doi.org/10.1038/nrneph.2014.87

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