Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte
injury phenotypes in glomerular disease.
Authors Yoo TH, Pedigo CE, Guzman J, Correa-Medina M, Wei C, Villarreal R, Mitrofanova
A, Leclercq F, Faul C, Li J, Kretzler M, Nelson RG, Lehto M, Forsblom C, Groop
PH, Reiser J, Burke GW, Fornoni A, Merscher S
Submitted By Alessia Fornoni on 1/6/2015
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2015
Date Published 1/1/2015
Volume : Pages 26 : 133 - 47
PubMed Reference 24925721
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 aVß3 integrin-dependent
migration in vitro. Furthermore, aVß3 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 aVß3 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 aVß3
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.

Investigators with authorship
Alessia FornoniUniversity of Miami - Medical Campus
Matthias KretzlerUniversity of Michigan