The phenomenon of acquired resistance to acute renal failure has been noted for close to a century and yet, it remains a poorly understood and poorly studied area. Among the contribution of the Principal Investigator to this area is his demonstration that resistance to injury resides at the cellular level and specifically, at the plasma membrane level and that neither hemodynamic factors, intraluminal factors no proximal tubular cell factors are responsible for such resistance at a cellular level. Particularly germane to this application is evidence that insults to the kidney activates the sphingomyelinase pathway and it is such activation that affords cytoresistance. Additionally, in relation to this , the Principal Investigator has demonstrated that depletion of injury-inducing proteins or injury- permissive proteins confer resistance and specifically, two such proteins, phospholipase 2 and calpain, when suppressed in terms of expression, can allow an injured cell to be resistant to subsequent insults. Finally, these investigators have demonstrated that the cytoresistant state is characterized by improvement in cellular energetics. Drawing upon these core observations, the principal investigator proposes three Specific Aims. The first Specific Aim analyzes the involvement to of the sphingomyelinase pathway in the development of cytoresistance.
This Specific Aim tests whether sphingomyelinase activity directly initiated the cytoresistant state and the timing of, and the mechanisms leading to sphingomyelinase activation.
This Specific Aim will also determine the functional effect of alteration in plasma membranes sphingolipid expression on vulnerability to injury, specifically addressing the changes in sphingolipid as a determinant of cytoresistance, the effect of altering GSL/sphingolipid on sensitivity to resistance, the role of flip/flop on membrane resistance.
This Specific Aim will also model vulnerability to injury with alterations in sphingolipid in model liposomal system and will conclude by extrapolating from these in vitro systems and the model systems to test the efficacy or lack thereof, of sphingosine and sphingosine analogs in initiating cytoresistance in vivo. The second Specific Aim will determine whether cytoresistance is mediated by depletion or altered trafficking of injury-inducing or injury- permissive proteins.
This Specific Aim rests on the thesis of the Principal Investigator that suppression of specific protein synthesis or increased catabolism, specifically, those proteins that are involved in initiating or sustaining cell injury, could render tissues resistant to subsequent damage.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Scherbenske, M James
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Fred Hutchinson Cancer Research Center
United States
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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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