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Kidney Week

Abstract: TH-PO791

SMPDL3b Regulates Proteinuria in Experimental Alport Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Mitrofanova, Alla, University of Miami, Miami, Florida, United States
  • Fontanella, Antonio Miguel, University of Miami, Miami, Florida, United States
  • Molina David, Judith T., University of Miami, Miami, Florida, United States
  • Varona Santos, Javier T., University of Miami, Miami, Florida, United States
  • Macrina, Lorenza, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • Burke, George William, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami, Miami, Florida, United States

Group or Team Name

  • Katz Family Division of Nephrology and Hypertension

Sphingosine-1-phosphate lyase insufficiency causes accumulation of sphingosine-1-phosphate (S1P) and is associated with focal segmental glomerulosclerosis (FSGS), that is often characterized by the recurrence of proteinuria after kidney transplantation. We previously reported that podocyte injury in recurrent FSGS is associated with downregulation of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), an enzyme localized in lipid raft domains that regulates lipid composition and plasma membrane fluidity. Alport syndrome (AS) is an inherited glomerular disease with FSGS-like lesions. In this study we tested the hypothesis that dysregulation of renal SMPDL3b expression affects the generation of bioactive sphingolipids thus contributing the renal disease in AS.


Mice with experimental AS (Col4a3-/- mice) were used in this study. To investigate the contribution of SMPDL3b to the renal phenotype in AS mice, AS mice were crossed to mice with podocyte-specific Smpdl3b deficiency to generate Smpdl3b deficient AS mice (DKO). Animals were sacrificed at 20 weeks of age for in-depth phenotypical analysis of kidneys. All animal studies were performed in accordance with the NIH IACUC Guide. For statistical analysis One-Way ANOVA followed by Bonferroni’s posttest was used.


Mice with experimental AS develop proteinuria at 4 weeks of age and die of renal failure at 25 weeks of age. We demonstrated that SMPDL3b expression is 7-fold increased in kidneys of AS mice compared to wildtype littermates. We found decreased albumin-creatinine ratio (6,091±4,098µg/mg) in DKO mice compared to AS mice (27,395±17,387µg/mg). Improved proteinuria was not associated with improved body weight, serum creatinine levels, glomerular filtration rate (130.5±51.5µl/min/100gBW in controls and 153.7±34.4µl/min/100gBW in double knockout) or renal histology. DKO mice also demonstrated significantly lower levels of S1P (0.07±0.01pmol/mg) in kidney cortexes compared to AS mice (0.17±0.04pmol/mg).


Our data indicate that SMPDL3b expression may affect availability of S1P and regulate proteinuria levels in experimental AS. Thus, targeting SMPDL3b expression levels in the kidney may represent a novel approach to improve renal outcome in patients with AS.


  • NIDDK Support