Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy

Joao Seda Neto, Atsunori Nakao, Hideyoshi Toyokawa, Michael A. Nalesnik, Anna Jeanine Romanosky, Kei Kimizuka, Takashi Kaizu, Naoki Hashimoto, Olga Azhipa, Donna B. Stolz, Augustine M K Choi, Noriko Murase

Research output: Contribution to journalArticle

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Abstract

Chronic allograft nephropathy (CAN) is the primary cause for late kidney allograft loss. Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against various stresses. We hypothesized that CO could minimize the chronic fibroinflammatory process and protect kidney allografts from CAN. Lewis kidney grafts were orthotopically transplanted into binephrectomized Brown-Norway rats under short-course tacrolimus. Recipients were maintained in room air or exposed to CO at 20 parts/million for 30 days after transplant. Efficacy of inhaled CO was studied at day 30 and day 80. Isografts maintained normal kidney function throughout the experiment with creatinine clearance of ∼1.5 ml/min. Renal allograft function in air controls progressively deteriorated, and creatinine clearance declined to 0.2 ± 0.1 ml/min by day 80 with substantial proteinuria. CO-treated animals had significantly better creatinine clearance (1.3 ± 0.2 ml/min) with minimal proteinuria. Histological examination revealed the development of progressive CAN in air-exposed grafts, whereas CO-treated grafts had minimal tubular atrophy and interstitial fibrosis, with negligible collagen IV deposition. In vitro analyses revealed that CO-treated recipients had significantly less T cell proliferation against donor peptides via the indirect allorecognition pathway and less anti-donor IgG antibodies compared with air controls. Intragraft mRNA levels for chemokines (regulated on activation normal T cell expressed and secreted, macrophage inflammatory protein-1α, chemokine receptors (CCR1, CXCR3, CXCR5), IL-2, and intercellular adhesion molecule-1 were significantly decreased in CO-treated than in air-treated allografts. Furthermore, reduction of blood flow in air-treated allografts was prevented with CO. In conclusion, inhaled CO at a low concentration efficiently abrogates chronic fibroinflammatory changes associated with CAN and improves long-term renal allograft function.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume290
Issue number2
DOIs
Publication statusPublished - Feb 2006
Externally publishedYes

Fingerprint

Carbon Monoxide
Inhalation
Allografts
Air
Kidney
Transplants
Creatinine
Proteinuria
Isografts
T-Lymphocytes
Macrophage Inflammatory Proteins
Heme Oxygenase (Decyclizing)
Chemokine Receptors
Tacrolimus
Intercellular Adhesion Molecule-1
Heme
Chemokines
Atrophy
Interleukin-2
Fibrosis

Keywords

  • Anti-inflammatory effect
  • Cytoprotection
  • Kidney transplantation

ASJC Scopus subject areas

  • Physiology

Cite this

Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. / Neto, Joao Seda; Nakao, Atsunori; Toyokawa, Hideyoshi; Nalesnik, Michael A.; Romanosky, Anna Jeanine; Kimizuka, Kei; Kaizu, Takashi; Hashimoto, Naoki; Azhipa, Olga; Stolz, Donna B.; Choi, Augustine M K; Murase, Noriko.

In: American Journal of Physiology - Renal Physiology, Vol. 290, No. 2, 02.2006.

Research output: Contribution to journalArticle

Neto, JS, Nakao, A, Toyokawa, H, Nalesnik, MA, Romanosky, AJ, Kimizuka, K, Kaizu, T, Hashimoto, N, Azhipa, O, Stolz, DB, Choi, AMK & Murase, N 2006, 'Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy', American Journal of Physiology - Renal Physiology, vol. 290, no. 2. https://doi.org/10.1152/ajprenal.00026.2005
Neto, Joao Seda ; Nakao, Atsunori ; Toyokawa, Hideyoshi ; Nalesnik, Michael A. ; Romanosky, Anna Jeanine ; Kimizuka, Kei ; Kaizu, Takashi ; Hashimoto, Naoki ; Azhipa, Olga ; Stolz, Donna B. ; Choi, Augustine M K ; Murase, Noriko. / Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. In: American Journal of Physiology - Renal Physiology. 2006 ; Vol. 290, No. 2.
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