Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease

J Am Soc Nephrol. 2015 Jan;26(1):133-47. doi: 10.1681/ASN.2013111213. Epub 2014 Jun 12.

Abstract

Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte αVβ3 integrin-dependent migration in vitro. Furthermore, αVβ3 integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent αVβ3 integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented αVβ3 integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.

Keywords: FSGS; diabetic nephropathy; glomerular disease; podocyte; proteinuria.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Movement
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Female
  • Gene Expression Regulation, Enzymologic*
  • HEK293 Cells
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Integrins / metabolism
  • Kidney Diseases / metabolism*
  • Kidney Glomerulus / injuries
  • Kidney Glomerulus / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neuropeptides / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Podocytes / cytology
  • Podocytes / pathology*
  • Receptors, Urokinase Plasminogen Activator / blood
  • Sphingomyelin Phosphodiesterase / metabolism*
  • rac1 GTP-Binding Protein / metabolism
  • rho GTP-Binding Proteins / metabolism
  • rhoA GTP-Binding Protein

Substances

  • Integrin alphaVbeta3
  • Integrins
  • Neuropeptides
  • Rac1 protein, mouse
  • Receptors, Urokinase Plasminogen Activator
  • SMPDL3B protein, human
  • Sphingomyelin Phosphodiesterase
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • sphingomyelinase-like phosphodiesterase 3b, mouse
  • RhoA protein, mouse
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein