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

TaeHyun Yoo, Christopher E. Pedigo, Johanna Guzman, Mayrin Correa-Medina, Changli Wei, Rodrigo Villarreal, Alla Mitrofanova, Farah Leclercq, Christian Faul, Jing Li, Matthias Kretzler, Robert G. Nelson, Markku Lehto, Carol Forsblom, Per Henrik Groop, Jochen Reiser, George William Burke, Alessia Fornoni, Sandra Merscher

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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.

Original languageEnglish
Pages (from-to)133-147
Number of pages15
JournalJournal of the American Society of Nephrology
Volume26
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

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Type 3 Cyclic Nucleotide Phosphodiesterases
Sphingomyelin Phosphodiesterase
Podocytes
Urokinase Plasminogen Activator Receptors
Diabetic Nephropathies
Phenotype
Wounds and Injuries
Integrins
Serum
Acids
Proteinuria
Chronic Kidney Failure
Apoptosis
Kidney
Biopsy

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Yoo, TaeHyun ; Pedigo, Christopher E. ; Guzman, Johanna ; Correa-Medina, Mayrin ; Wei, Changli ; Villarreal, Rodrigo ; Mitrofanova, Alla ; Leclercq, Farah ; Faul, Christian ; Li, Jing ; Kretzler, Matthias ; Nelson, Robert G. ; Lehto, Markku ; Forsblom, Carol ; Groop, Per Henrik ; Reiser, Jochen ; Burke, George William ; Fornoni, Alessia ; Merscher, Sandra. / Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 1. pp. 133-147.
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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.",
author = "TaeHyun Yoo and Pedigo, {Christopher E.} and Johanna Guzman and Mayrin Correa-Medina and Changli Wei and Rodrigo Villarreal and Alla Mitrofanova and Farah Leclercq and Christian Faul and Jing Li and Matthias Kretzler and Nelson, {Robert G.} and Markku Lehto and Carol Forsblom and Groop, {Per Henrik} and Jochen Reiser and Burke, {George William} and Alessia Fornoni and Sandra Merscher",
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Yoo, T, 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 2015, 'Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease', Journal of the American Society of Nephrology, vol. 26, no. 1, pp. 133-147. https://doi.org/10.1681/ASN.2013111213

Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. / Yoo, TaeHyun; Pedigo, Christopher E.; Guzman, Johanna; Correa-Medina, Mayrin; Wei, Changli; Villarreal, Rodrigo; Mitrofanova, Alla; Leclercq, Farah; Faul, Christian; Li, Jing; Kretzler, Matthias; Nelson, Robert G.; Lehto, Markku; Forsblom, Carol; Groop, Per Henrik; Reiser, Jochen; Burke, George William; Fornoni, Alessia; Merscher, Sandra.

In: Journal of the American Society of Nephrology, Vol. 26, No. 1, 01.01.2015, p. 133-147.

Research output: Contribution to journalArticle

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T1 - Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease

AU - Yoo, TaeHyun

AU - Pedigo, Christopher E.

AU - Guzman, Johanna

AU - Correa-Medina, Mayrin

AU - Wei, Changli

AU - Villarreal, Rodrigo

AU - Mitrofanova, Alla

AU - Leclercq, Farah

AU - Faul, Christian

AU - Li, Jing

AU - Kretzler, Matthias

AU - Nelson, Robert G.

AU - Lehto, Markku

AU - Forsblom, Carol

AU - Groop, Per Henrik

AU - Reiser, Jochen

AU - Burke, George William

AU - Fornoni, Alessia

AU - Merscher, Sandra

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

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