From a worldwide perspective, the crush syndrome is a leading cause of acute renal failure (ARF). Both myoglobinuria (Mgb) and intravascular volume depletion/renal ischemia are critical to its pathogenesis because they induce synergistic tubular damage. However, the pathophysiologic basis for this Mgb- ischemic interaction, as it exists at the renal vascular/endothelial cell, and tubular cell/tubular cell membrane level has not been well defined. The goal of this research is to explore its basis such that better therapeutic modalities can be designed. The proposal has three specific aims: Goal 1: Define why Mgb and renal hypoperfusion cause synergistic tubular ATP depletion, thereby intensifying cellular necrosis. Work completed by this laboratory indicates that Mgb exacerbates volume depletion induced renal tubular ATP depletion by intensifying renal vasoconstriction and by inducing a primary disturbance in cellular energetics. Causes for these abnormalities will be explored using whole animal, cultured endothelial cell, and Mgb loaded isolated proximal tubular segment experiments. Goal 2: Determine the role of reactive oxygen species (ROS) in the Mgb-ischemic interaction. Controversy exists as to whether ROS are mediators of Mgburic and ischemic ARF. Using in vitro and in vivo models, this proposal will assess: 1) mechanisms by which inorganic Fe2+ induces cytotoxicity to isolated proximal tubular segments (PTS); 2) assess whether Mgb loading of PTS generates hydroxyl radical and H2O2 which then sensitize them to superimposed oxidant challenges and to in vitro anoxic/reoxygenation injury; and 3) determine whether Mgb and ischemia cause in vivo synergistic oxidant stress, helping to explain the Mgb-ischemic interaction. Goal 3: Determine the influence of protein endocytosis on ischemic renal injury. In 1986, this laboratory demonstrated that protein endocytosis, per se, sensitizes the kidney to superimposed ischemic injury. Thus, Mgb toxicity may not be Fe dependent. Recent data indicate that protein endocytosis alters brush border membrane (BBM) susceptibility to both in vivo and in vitro injury. Thus, the effect of endocytosis on 1) BBM structure, function, and responses to in vitro degradative reactions will be sought; and 2) the influence of a) active protein transport, and b) lysosomal protein storage on the evolution of ischemic tissue damage will be assessed. By addressing the above, new insights into heme protein/low molecular weight protein nephrotoxicity and shock-induced renal damage will be obtained which should have direct relevance to crush syndrome induced ARF.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038432-08
Application #
2140526
Study Section
Pathology A Study Section (PTHA)
Project Start
1988-03-01
Project End
1997-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Zager, Richard A (2017) Alpha 1 Microglobulin: A Potentially Paradoxical Anti-Oxidant Agent. Adv Tech Biol Med 5:
Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B (2016) Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure. Kidney Int 90:67-76
Mar, Daniel; Gharib, Sina A; Zager, Richard A et al. (2015) Heterogeneity of epigenetic changes at ischemia/reperfusion- and endotoxin-induced acute kidney injury genes. Kidney Int 88:734-44
Zager, Richard A (2015) Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration. Transl Res 166:485-501
Zager, Richard A (2014) Progression from acute kidney injury to chronic kidney disease: clinical and experimental insights and queries. Nephron Clin Pract 127:46-50
Johnson, Ali C M; Zager, Richard A (2014) Renal cortical pyruvate as a potentially critical mediator of acute kidney injury. Nephron Clin Pract 127:129-32
Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B (2014) Acute hepatic ischemic-reperfusion injury induces a renal cortical ""stress response,"" renal ""cytoresistance,"" and an endotoxin hyperresponsive state. Am J Physiol Renal Physiol 307:F856-68
Zager, Richard A; Johnson, Ali C M; Becker, Kirsten (2014) Renal cortical pyruvate depletion during AKI. J Am Soc Nephrol 25:998-1012
Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B (2014) Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury. PLoS One 9:e98380
Zager, Richard A; Johnson, Ali C M; Becker, Kirsten (2013) Renal Cortical Lactate Dehydrogenase: A Useful, Accurate, Quantitative Marker of In Vivo Tubular Injury and Acute Renal Failure. PLoS One 8:e66776

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