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About the Authors:
Richard A. Zager
* E-mail: [email protected]
Affiliation: The Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, Washington, United States of America
Ali C. M. Johnson
Affiliation: The Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, Washington, United States of America
Kirsten B. Frostad
Affiliation: The Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, Washington, United States of America
Introduction
Acute kidney injury (AKI) up-regulates a variety of stress proteins which can serve as biomarkers of that injury, and potentially impact the course of evolving tissue damage. Well documented examples include neutrophil gelatinase- associated lipocalin (NGAL) [1], [2], kidney injury molecule-1 (KIM-1) [3], [4], L type fatty acid binding protein (L- FABP) [5], [6], and heat shock proteins, e.g., heme oxygenase-1 [7]. In a recent series of studies [8]–[10], we made the surprising observation that, in addition to the above, three stress proteins that are either exclusively, or predominantly, expressed in liver (α-fetoprotein, haptoglobin, hemopexin), are also rapidly induced in mouse proximal tubules in response to ischemic and toxic (maleate, glycerol, and cisplatin) AKI. This was denoted by the following observations: i) AKI increased each of their respective mRNAs; ii) a concomitant increase in RNA polymerase II binding to these gene(s) occurred (implying increased transcription); and iii) marked increases in each of these proteins were documented within renal cortical proximal tubules. Of great interest was that the degrees of increase following experimental AKI were comparable to those observed for NGAL, a classic AKI biomarker gene. This underscored the robust nature of these responses [8]–[10]. To determine whether a clinical correlate of these experimental findings existed, urinary levels of α-fetoprotein and haptoglobin were measured in patients with AKI, and marked increases (again, comparable to those seen for NGAL) were observed [9], [10]. Based on these findings, we coined the term “renal hepatization”, i.e., in which the injured kidney assumes selected features of a hepatic phenotype [8]–[10]. That the normally silent albumin gene was also up-regulated in renal cortex following AKI induction [10] further supported the existence of this “renal hepatization” phenomenon.
A fourth hepatic stress protein is α-1 antitrypsin (AAT) [11], [12]. Thus, with acute liver injury, increased AAT production, with corresponding plasma AAT elevations,...