Abstract

Ischemia/reperfusion injury is caused by activation of cytotoxic and inflammatory cascades during the reperfusion period. Injury in experimental animals can be modestly decreased by inhibition of either of these two pathways. They recently found the a-MSH protects against severe renal ischemia/reperfusion injury, even when started during the reperfusion period. a-MSH is a neuropeptide with broad anti-inflammatory properties. They found that a-MSH inhibits the synthesis of cytokines, chemoattractive chemokines and NO. It is not known why a-MSH is so effective in preventing ischemia/reperfusion injury. They hypothesize that a-MSH prevents the maladaptive activation of both the cytotoxic (NO) and inflammatory (neutrophile) cascade. They will investigate the following Specific Aims:
In Aim #1, they will define the spectrum of activity of a-MSH in treating ischemia/reperfusion injury. They will determine when a-MSH is active during the reperfusion period and if a-MSH accelerates recovery from established renal failure.
In Aim #2, they will localize the MSH receptors to specific portions of the nephron and vasculature using in situ hybridization and RT/PCR. They will also determine where a-MSH is produced.
In Aim #3, they will determine the effect of a-MSH on ischemia induced cytotoxicity mediated by NO. They have preliminary evidence that a-MSH inhibits the production of iNOS during ischemia/reperfusion. They will determine if NO is responsible for tissue injury in kidneys, isolated perfused kidneys and isolated tubules subjected to ischemia.
In Aim #4, they will determine the effect of a-MSH on the ischemia-induced injury mediated by neutrophiles. They will study the effect of a-MSH on neutrophile infiltration, expression of renal chemattractants and endothelial cell adhesion molecules in the ischemic models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045923-08
Application #
6138005
Study Section
General Medicine B Study Section (GMB)
Program Officer
Scherbenske, M James
Project Start
1993-01-01
Project End
2000-08-31
Budget Start
2000-01-01
Budget End
2000-08-31
Support Year
8
Fiscal Year
2000
Total Cost
$14,877
Indirect Cost

  Institution

Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390

  Publications

Muramatsu, Yasunari; Tsujie, Michiko; Kohda, Yukimasa et al. (2002) Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int 62:1601-10
Deng, J; Kohda, Y; Chiao, H et al. (2001) Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int 60:2118-28
Honig, L S (2000) Inflammation in neurodegenerative disease: good, bad, or irrelevant? Arch Neurol 57:786-8
Honig, L S; Chambliss, D D; Bigio, E H et al. (2000) Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls. Neurology 55:1082-8
Honig, L S; Rosenberg, R N (2000) Apoptosis and neurologic disease. Am J Med 108:317-30
Kohda, Y; Murakami, H; Moe, O W et al. (2000) Analysis of segmental renal gene expression by laser capture microdissection. Kidney Int 57:321-31
Chiao, H; Kohda, Y; McLeroy, P et al. (1998) Alpha-melanocyte-stimulating hormone inhibits renal injury in the absence of neutrophils. Kidney Int 54:765-74
Tank, J E; Moe, O W; Henrich, W L (1998) Abnormal regulation of proximal tubule renin mRNA in the Dahl/Rapp salt-sensitive rat. Kidney Int 54:1608-16
Star, R A (1998) Treatment of acute renal failure. Kidney Int 54:1817-31
Chiao, H; Kohda, Y; McLeroy, P et al. (1997) Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest 99:1165-72

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