| Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. | |
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MedLine Citation:
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PMID: 19369289 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Chronic allograft nephropathy (CAN) represents progressive deterioration of renal allograft function with fibroinflammatory changes. CAN, recently reclassified as interstitial fibrosis (IF) and tubular atrophy (TA) with no known specific etiology, is a major cause of late renal allograft loss and remains a significant deleterious factor of successful renal transplantation. Carbon monoxide (CO), an effector byproduct of heme oxygenase pathway, is known to have potent anti-inflammatory and antifibrotic functions. We hypothesized that inhaled CO would inhibit fibroinflammatory process of CAN and restore renal allograft function, even when the treatment was initiated after CAN was established. Lewis rat kidney grafts were orthotopically transplanted into binephrectomized allogenic Brown Norway rats under brief tacrolimus (0.5 mg/kg im, days 0-6). At day 60, CO (20 ppm) inhalation was initiated to recipients and continued until day 150 or animal death. Development of CAN was confirmed at day 60 with decreased creatinine clearance (CCr), significant proteinuria, and histopathological findings of TA, IF, and intimal arteritis. Air-treated control recipients continued to deteriorate with further declines of CCr and increases of urinary protein excretion and died with a median survival of 82 days. In contrast, progression of CAN was decelerated when recipients received CO on days 60-150, showing markedly improved graft histopathology, restored renal function, and improved recipient survival to a median of >150 days. CO significantly reduced intragraft mRNA levels for IFN-gamma and TNF-alpha at day 90. Expression of profibrotic TGF-beta/Smad was significantly suppressed with CO, together with downregulation of ERK-MAPK pathways. Continuous CO (20 ppm) treatment for days 0-30, days 30-60, or days 0-90, or daily 1-h CO (250 ppm) treatment for days 0-90, also showed efficacy in inhibiting CAN. The study demonstrates that CO is able to inhibit progression of fibroinflammatory process of CAN, restore renal allograft function, and improve survival even when the treatment is started after CAN is diagnosed. |
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Authors:
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Atsunori Nakao; Gaetano Faleo; Michael A Nalesnik; Joao Seda-Neto; Junichi Kohmoto; Noriko Murase |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-04-15 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 297 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-06-25 Completed Date: 2009-08-20 Revised Date: 2011-04-28 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F19-26 Citation Subset: IM |
Affiliation:
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Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atrophy / prevention & control Carbon Monoxide / pharmacology* Chronic Disease Disease Models, Animal Disease Progression Dose-Response Relationship, Drug Fibrosis / prevention & control Graft Rejection / prevention & control Interferon-gamma / metabolism Kidney Diseases / metabolism, pathology, prevention & control* Kidney Transplantation / pathology*, physiology* Male Rats Rats, Inbred BN Rats, Inbred Lew Transplantation, Homologous Tumor Necrosis Factor-alpha / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK-071753/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Tumor Necrosis Factor-alpha; 630-08-0/Carbon Monoxide; 82115-62-6/Interferon-gamma |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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