A seeming paradox exists during the maintenance phase of acute renal failure (ARF). On the one hand, diverse forms of acute tubular injury evoke adaptive responses that protect the kidney from further damage (so called """"""""acquired cytoresistance""""""""). Presumably, this protection confers a survival advantage, both at the whole organ, and whole animal, level. On the other hand, a potentially countervailing consequence of ARF is that the kidney hyper-responds to diverse Toll like receptor (TLR) ligands, most notably lipopolysaccharide (LPS). This causes exaggerated LPS- driven cytokine and chemokine (e.g., TNF-a / MCP- 1) production. As a result, profound increases in intra-renal levels of these pro-inflammatory mediators develop, potentially slowing ARF recovery. Furthermore, with cytokine efflux into renal venous blood, striking increases in circulating cytokine / chemokine levels develop. This can contribute to extra-renal tissue damage (e.g., in lung, liver, heart, and brain;i.e., """"""""organ cross-talk""""""""), and thus, predispose to multi-organ failure (MOF). The clinical relevance of these events is underscored by the fact that Gram negative sepsis and MOF are leading causes of death in patients with ARF. This application hypothesizes that these two ARF maintenance phase phenomena (cytoresistance;TLR hyper-responsiveness) are examples of """"""""biologic memory"""""""": i.e., whereby one episode of renal injury 're-programs'the kidney to 'remember'the initial insult, and thus, produce altered tissue responses upon re-challenge. Over the past 3 years, the PI has tested the hypothesis that this """"""""biologic memory"""""""" is expressed at the genomic level, and that these genomic changes help determine how the ARF kidney responds to subsequent insults. To support this concept, we have identified """"""""activating"""""""" histone changes at specific genes that participate in both acquired cytoresistance (heme oxygenase 1, HMG CoA reductase), and the hyper-inflammatory state (TNF-a;MCP-1). During the resolution phase of ARF, the histone changes at these pro-inflammatory genes and their cognate mRNAs progressively increase. Conversely, cytoresistant gene expression progressively abates. These reciprocal shifting patterns, i.e., increasing inflammatory gene expression / decreasing cytoresistance gene expression, can delay ARF recovery. Hence, the overall aims of the proposed investigation are as follows: 1. Delineate which specific cell injury pathways (e.g., ATP depletion, oxidant stress, phospholipid hydrolysis) are the initial stimuli that trigger downstream histone alterations;2. Determine whether histone changes occur at test gene promoter regions, and whether hyper-recruitment of relevant transcription factors and of RNA polymerase II (Pol II) to them result;3. Ascertain the histone-modifying machineries that induce these histone alterations;and 4. Using the information gleaned from the above, test the mechanistic relevance of these pathways to the cytoresistance and the hyper-inflammatory states. By so doing, new insights into ischemia- induced tissue modifications, with implications for subsequent tissue injury, will result.

Public Health Relevance

This application addresses how pre-existent acute kidney injury alters how the kidney responds to further injury events. One the one hand, pre-existent injury ushers in protective mechanisms that mitigate further lethal damage;on the other hand, the injured kidney hyper-responds to inflammatory molecules, and this has implications for both the kidney and the rest of the body. This application addresses the mechanisms by which these changes occur, and how they can be altered to enhance kidney recovery.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Kimmel, Paul
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Fred Hutchinson Cancer Research Center
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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; Becker, Kirsten (2013) Post-ischemic azotemia as a partial 'brake', slowing progressive kidney disease. Nephrol Dial Transplant 28:1455-62

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