title: Proximal tubule haptoglobin gene activation is an integral component of the acute kidney injury "stress response".
abstract: Haptoglobin (Hp) synthesis occurs almost exclusively in liver, and it is rapidly upregulated in response to stress. Because many of the pathways that initiate hepatic Hp synthesis are also operative during acute kidney injury (AKI), we tested whether AKI activates the renal cortical Hp gene. CD-1 mice were subjected to six diverse AKI models: ischemia-reperfusion, glycerol injection, cisplatin nephrotoxicity, myoglobinuria, endotoxemia, and bilateral ureteral obstruction. Renal cortical Hp gene induction was determined either 4-72 h or 1-3 wk later by measuring Hp mRNA and protein levels. Relative renal vs. hepatic Hp gene induction during endotoxemia was also assessed. Each form of AKI induced striking and sustained Hp mRNA increases, leading to ∼10- to 100-fold renal Hp protein elevations (ELISA; Western blot). Immunohistochemistry, and isolated proximal tubule assessments, indicated that the proximal tubule was the dominant (if not only) site of the renal Hp increases. Corresponding urinary and plasma Hp elevations were surrogate markers of this response. Endotoxemia evoked 25-fold greater Hp mRNA increases in kidney vs. liver, indicating marked renal Hp gene reactivity. Clinical relevance of these findings was suggested by observations that urine samples from 16 patients with established AKI had statistically higher (∼12×) urinary Hp levels than urine samples from either normal subjects or from 15 patients with chronic kidney disease. These AKI-associated urinary Hp increases mirrored those seen for urinary neutrophil gelatinase-associated lipoprotein, a well accepted AKI biomarker gene. In summary, these studies provide the first evidence that AKI evokes rapid, marked, and sustained induction of the proximal tubule Hp gene. Hp's known antioxidant, as well as its protean pro- and anti-inflammatory, actions imply potentially diverse effects on the evolution of acute tubular injury.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. dzager@fhcrc.org
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.forename: Anitha
authors.initials: A
authors.lastname: Vijayan
authors.forename: Ali C M
authors.initials: AC
authors.lastname: Johnson
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D000209:Acute-Phase Proteins / Q000378:metabolism; D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015427:Reperfusion Injury / Q000378:metabolism; D015533:Transcriptional Activation; D014517:Ureteral Obstruction / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D006242:Haptoglobins