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

Krishna M. Boini, Min Xia, Caixia Li, Chun Zhang, Lori P. Payne, Justine M. Abais, Justin L. Poklis, Philip B. Hylemon, Pin Lan Li

Research output: Contribution to journalArticle

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 oxidaseassociated local oxidative stress during hHcys.

Original languageEnglish (US)
Pages (from-to)2210-2219
Number of pages10
JournalAmerican Journal of Pathology
Volume179
Issue number5
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Fingerprint

Type A Niemann-Pick Disease
Sphingomyelin Phosphodiesterase
Hyperhomocysteinemia
Acids
Wounds and Injuries
Genes
Ceramides
Folic Acid
Small Interfering RNA
Oxidative Stress
Sclerosis
Diet
NADP
Kidney
Podocytes
Molecular Imaging
Desmin
NADPH Oxidase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia- induced glomerular injury in mice. / Boini, Krishna M.; Xia, Min; Li, Caixia; Zhang, Chun; Payne, Lori P.; Abais, Justine M.; Poklis, Justin L.; Hylemon, Philip B.; Li, Pin Lan.

In: American Journal of Pathology, Vol. 179, No. 5, 01.11.2011, p. 2210-2219.

Research output: Contribution to journalArticle

Boini, KM, Xia, M, Li, C, Zhang, C, Payne, LP, Abais, JM, Poklis, JL, Hylemon, PB & Li, PL 2011, 'Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia- induced glomerular injury in mice', American Journal of Pathology, vol. 179, no. 5, pp. 2210-2219. https://doi.org/10.1016/j.ajpath.2011.07.019
Boini, Krishna M. ; Xia, Min ; Li, Caixia ; Zhang, Chun ; Payne, Lori P. ; Abais, Justine M. ; Poklis, Justin L. ; Hylemon, Philip B. ; Li, Pin Lan. / Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia- induced glomerular injury in mice. In: American Journal of Pathology. 2011 ; Vol. 179, No. 5. pp. 2210-2219.
@article{fd3599ab0b314b12b8a2d1e0ae9cab9b,
title = "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 oxidaseassociated local oxidative stress during hHcys.",
author = "Boini, {Krishna M.} and Min Xia and Caixia Li and Chun Zhang and Payne, {Lori P.} and Abais, {Justine M.} and Poklis, {Justin L.} and Hylemon, {Philip B.} and Li, {Pin Lan}",
year = "2011",
month = "11",
day = "1",
doi = "10.1016/j.ajpath.2011.07.019",
language = "English (US)",
volume = "179",
pages = "2210--2219",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia- induced glomerular injury in mice

AU - Boini, Krishna M.

AU - Xia, Min

AU - Li, Caixia

AU - Zhang, Chun

AU - Payne, Lori P.

AU - Abais, Justine M.

AU - Poklis, Justin L.

AU - Hylemon, Philip B.

AU - Li, Pin Lan

PY - 2011/11/1

Y1 - 2011/11/1

N2 - 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 oxidaseassociated local oxidative stress during hHcys.

AB - 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 oxidaseassociated local oxidative stress during hHcys.

UR - http://www.scopus.com/inward/record.url?scp=80055009378&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80055009378&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2011.07.019

DO - 10.1016/j.ajpath.2011.07.019

M3 - Article

C2 - 21893018

AN - SCOPUS:80055009378

VL - 179

SP - 2210

EP - 2219

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 5

ER -