Cyclophilin D gene ablation protects mice from ischemic renal injury

Kishor Devalaraja-Narashimha, Alicia M Schiller, Babu J Padanilam

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Increased oxidative stress and intracellular calcium levels and mitochondrial overloading of calcium during ischemic renal injury (IRI) favor mitochondrial membrane permeability transition pore (MPTP) opening and subsequent necrotic cell death. Cyclophilin D (CypD) is an essential component of MPTP, and recent findings implicate its role in necrotic, but not apoptotic, cell death. To evaluate the role of CypD following IRI, we tested the hypothesis that CypD gene ablation protects mice from IRI. Renal function as assessed by plasma levels of both creatinine and blood urea nitrogen was significantly reduced in CypD knockout (CypD-/-) mice compared with wild-type mice during the 5-day post-ischemia period. Erythrocyte trapping, tubular cell necrosis, tubular dilatation, and neutrophil infiltration were significantly decreased in CypD-/- mice. To define the mechanisms by which CypD deficiency protect the kidneys, an in vitro model of IRI was employed. Inhibition of CypD using Cyclosporin A in oxidant-injured cultured proximal tubular cells (PTC) prevented mitochondrial membrane depolarization, reduced LDH release, ATP depletion and necrotic cell death. Similarly, oxidant-injured CypD-/- PTC primary cultures were protected from cytotoxicity and necrosis. To conclude, CypD gene ablation offers both functional and morphological protection in mice following IRI by decreasing necrotic cell death possibly via inhibition of MPTP and ATP depletion.

Original languageEnglish (US)
Pages (from-to)F749-F759
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 1 2009

Fingerprint

Kidney
Wounds and Injuries
Genes
Cell Death
Mitochondrial Membranes
Oxidants
Permeability
Necrosis
Adenosine Triphosphate
Calcium
cyclophilin D
Primary Cell Culture
Membranes
Neutrophil Infiltration
Blood Urea Nitrogen
Knockout Mice
Cyclosporine
Dilatation
Creatinine
Oxidative Stress

Keywords

  • ATP depletion
  • Acute renal failure
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Cyclophilin D gene ablation protects mice from ischemic renal injury. / Devalaraja-Narashimha, Kishor; Schiller, Alicia M; Padanilam, Babu J.

In: American Journal of Physiology - Renal Physiology, Vol. 297, No. 3, 01.09.2009, p. F749-F759.

Research output: Contribution to journalArticle

@article{94abf8b8160f494c8dc062c02f6a1059,
title = "Cyclophilin D gene ablation protects mice from ischemic renal injury",
abstract = "Increased oxidative stress and intracellular calcium levels and mitochondrial overloading of calcium during ischemic renal injury (IRI) favor mitochondrial membrane permeability transition pore (MPTP) opening and subsequent necrotic cell death. Cyclophilin D (CypD) is an essential component of MPTP, and recent findings implicate its role in necrotic, but not apoptotic, cell death. To evaluate the role of CypD following IRI, we tested the hypothesis that CypD gene ablation protects mice from IRI. Renal function as assessed by plasma levels of both creatinine and blood urea nitrogen was significantly reduced in CypD knockout (CypD-/-) mice compared with wild-type mice during the 5-day post-ischemia period. Erythrocyte trapping, tubular cell necrosis, tubular dilatation, and neutrophil infiltration were significantly decreased in CypD-/- mice. To define the mechanisms by which CypD deficiency protect the kidneys, an in vitro model of IRI was employed. Inhibition of CypD using Cyclosporin A in oxidant-injured cultured proximal tubular cells (PTC) prevented mitochondrial membrane depolarization, reduced LDH release, ATP depletion and necrotic cell death. Similarly, oxidant-injured CypD-/- PTC primary cultures were protected from cytotoxicity and necrosis. To conclude, CypD gene ablation offers both functional and morphological protection in mice following IRI by decreasing necrotic cell death possibly via inhibition of MPTP and ATP depletion.",
keywords = "ATP depletion, Acute renal failure, Mitochondria",
author = "Kishor Devalaraja-Narashimha and Schiller, {Alicia M} and Padanilam, {Babu J}",
year = "2009",
month = "9",
day = "1",
doi = "10.1152/ajprenal.00239.2009",
language = "English (US)",
volume = "297",
pages = "F749--F759",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
number = "3",

}

TY - JOUR

T1 - Cyclophilin D gene ablation protects mice from ischemic renal injury

AU - Devalaraja-Narashimha, Kishor

AU - Schiller, Alicia M

AU - Padanilam, Babu J

PY - 2009/9/1

Y1 - 2009/9/1

N2 - Increased oxidative stress and intracellular calcium levels and mitochondrial overloading of calcium during ischemic renal injury (IRI) favor mitochondrial membrane permeability transition pore (MPTP) opening and subsequent necrotic cell death. Cyclophilin D (CypD) is an essential component of MPTP, and recent findings implicate its role in necrotic, but not apoptotic, cell death. To evaluate the role of CypD following IRI, we tested the hypothesis that CypD gene ablation protects mice from IRI. Renal function as assessed by plasma levels of both creatinine and blood urea nitrogen was significantly reduced in CypD knockout (CypD-/-) mice compared with wild-type mice during the 5-day post-ischemia period. Erythrocyte trapping, tubular cell necrosis, tubular dilatation, and neutrophil infiltration were significantly decreased in CypD-/- mice. To define the mechanisms by which CypD deficiency protect the kidneys, an in vitro model of IRI was employed. Inhibition of CypD using Cyclosporin A in oxidant-injured cultured proximal tubular cells (PTC) prevented mitochondrial membrane depolarization, reduced LDH release, ATP depletion and necrotic cell death. Similarly, oxidant-injured CypD-/- PTC primary cultures were protected from cytotoxicity and necrosis. To conclude, CypD gene ablation offers both functional and morphological protection in mice following IRI by decreasing necrotic cell death possibly via inhibition of MPTP and ATP depletion.

AB - Increased oxidative stress and intracellular calcium levels and mitochondrial overloading of calcium during ischemic renal injury (IRI) favor mitochondrial membrane permeability transition pore (MPTP) opening and subsequent necrotic cell death. Cyclophilin D (CypD) is an essential component of MPTP, and recent findings implicate its role in necrotic, but not apoptotic, cell death. To evaluate the role of CypD following IRI, we tested the hypothesis that CypD gene ablation protects mice from IRI. Renal function as assessed by plasma levels of both creatinine and blood urea nitrogen was significantly reduced in CypD knockout (CypD-/-) mice compared with wild-type mice during the 5-day post-ischemia period. Erythrocyte trapping, tubular cell necrosis, tubular dilatation, and neutrophil infiltration were significantly decreased in CypD-/- mice. To define the mechanisms by which CypD deficiency protect the kidneys, an in vitro model of IRI was employed. Inhibition of CypD using Cyclosporin A in oxidant-injured cultured proximal tubular cells (PTC) prevented mitochondrial membrane depolarization, reduced LDH release, ATP depletion and necrotic cell death. Similarly, oxidant-injured CypD-/- PTC primary cultures were protected from cytotoxicity and necrosis. To conclude, CypD gene ablation offers both functional and morphological protection in mice following IRI by decreasing necrotic cell death possibly via inhibition of MPTP and ATP depletion.

KW - ATP depletion

KW - Acute renal failure

KW - Mitochondria

UR - http://www.scopus.com/inward/record.url?scp=69449096248&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69449096248&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00239.2009

DO - 10.1152/ajprenal.00239.2009

M3 - Article

C2 - 19553348

AN - SCOPUS:69449096248

VL - 297

SP - F749-F759

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 0363-6127

IS - 3

ER -