Following heterogeneous forms of experimental renal injury (e.g., nephrotoxins, ischemia, urinary tract obstruction), proximal tubules undergo adaptive changes which protect them from further attack. This can either prevent a worsening of established acute renal failure (ARF), or block recurrent episodes. Characteristics of this """"""""acquired cytoresistance"""""""" (AC) are that: 1) it requires about 18 hrs to develop; 2) it is expressed against diverse forms of secondary insults; 3) it can protect for at least 30 days; 4) it does not require de novo protein synthesis; and 5) it is mediated by a fundamental change within the proximal tubular plasma (and possibly mitochondrial) membrane(s), conferring cellular protection against further attack. Recent work from this laboratory has identified increased tubular membrane cholesterol expression following renal injury, and this is critical to the AC state. Given the broad based biologic relevance of AC (e.g., it can also contribute to cancer cell resistance to chemotherapy), this proposal has the following 3 Specific Aims: 1. Determine the mechanisms for, and nature of. the cholesterol elevations in the AC state: a) do the cholesterol elevations arise from increased synthesis, increased uptake, or decreased efflux? b) do the cholesterol increments reflect elevations of free vs. esterifled cholesterol pool(s)? and c) what subcellular cholesterol distribution patterns result? 2. Determine mechanisms by which cholesterol mediates AC: a) which cholesterol moieties (e.g. free vs. esterifled) confer AC? b) do they, how do they, increase membrane resistance to attack?; and c) is there a mechanistic link between increased cell cholesterol and improved mitochondrial performance in the AC state? 3. Define whether AC is impacted by two cholesterol- associated signaling pathways: Specifically, do the """"""""upstream"""""""" mevalonate pathway and/or the """"""""downstream"""""""" cholesterol/sphingomyelin microdomain (raft/caveolae) pathway impact the emergence, or expression, of the AC state? The ultimate goal of these experiments is to better define cellular adaptations to injury in an attempt to devise prophylactic strategies to either increase (or, in the case of cancer chemotherapy, decrease) cellular resistance to superimposed attack.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK038432-16
Application #
6620203
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wilder, Elizabeth L
Project Start
1988-03-01
Project End
2006-12-31
Budget Start
2003-03-01
Budget End
2003-12-31
Support Year
16
Fiscal Year
2003
Total Cost
$365,895
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
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
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; Becker, Kirsten (2013) Post-ischemic azotemia as a partial 'brake', slowing progressive kidney disease. Nephrol Dial Transplant 28:1455-62
Ruiz, Stacey; Pergola, Pablo E; Zager, Richard A et al. (2013) Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 83:1029-41
Zager, Richard A; Johnson, Ali C M; Andress, Dennis et al. (2013) Progressive endothelin-1 gene activation initiates chronic/end-stage renal disease following experimental ischemic/reperfusion injury. Kidney Int 84:703-12

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