Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia-induced glomerular injury in mice.

Abstract

Hyperhomocysteinemia (hHcys) enhances ceramide production, leading to the activation of NADPH oxidase and consequent glomerular oxidative stress and sclerosis. The present study was performed to determine whether acid sphingomyelinase (Asm), a ceramide-producing enzyme, is implicated in the development of hHcys-induced glomerular oxidative stress and injury. Uninephrectomized Asm-knockout (Asm(-/-)) and wild-type (Asm(+/+)) mice, with or without Asm short hairpin RNA (shRNA) transfection, were fed a folate-free (FF) diet for 8 weeks, which significantly elevated the plasma Hcys level compared with mice fed normal chow. By using in vivo molecular imaging, we found that transfected shRNAs were expressed in the renal cortex starting on day 3 and continued for 24 days. The FF diet significantly increased renal ceramide production, Asm mRNA and activity, urinary total protein and albumin excretion, glomerular damage index, and NADPH-dependent superoxide production in the renal cortex from Asm(+/+) mice compared with that from Asm(-/-) or Asm shRNA-transfected wild-type mice. Immunofluorescence analysis showed that the FF diet decreased the expression of podocin but increased desmin and ceramide levels in glomeruli from Asm(+/+) mice but not in those from Asm(-/-) and Asm shRNA-transfected wild-type mice. In conclusion, our observations reveal that Asm plays a pivotal role in mediating podocyte injury and glomerular sclerosis associated with NADPH oxidase-associated local oxidative stress during hHcys.

• Authors: Krishna M Boini, Min Xia, Caixia Li, Chun Zhang, Lori P Payne, Justine M Abais, Justin L Poklis, Philip B Hylemon, Pin-Lan Li
• Journal: The American journal of pathology (Am J Pathol) Vol. 179 Issue 5 Pg. 2210-9 (Nov 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21893018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Ceramides
• Superoxides
• Sphingomyelin Phosphodiesterase

Topics

• Animals
• Cells, Cultured
• Ceramides (metabolism)
• Gene Silencing (physiology)
• Gene Transfer Techniques
• Hyperhomocysteinemia (complications)
• Kidney Diseases (enzymology, genetics)
• Kidney Glomerulus (enzymology)
• Mice
• Mice, Inbred C57BL
• Microbubbles
• Oxidative Stress (genetics)
• Sphingomyelin Phosphodiesterase (deficiency, genetics, metabolism)
• Superoxides (metabolism)