Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury.
Alpha-1-antitrypsin (AAT) is a hepatic stress protein with protease inhibitor activity. Recent evidence indicates that ischemic or toxic injury can evoke selective changes within kidney that resemble a hepatic phenotype. Hence, we tested the following: i) Does acute kidney injury (AKI) up-regulate the normally renal silent AAT gene? ii) Does rapid urinary AAT excretion result? And iii) Can AAT's anti-protease/anti-neutrophil elastase (NE) activity protect injured proximal tubule cells? CD-1 mice were subjected to ischemic or nephrotoxic (glycerol, maleate, cisplatin) AKI. Renal functional and biochemical assessments were made 4-72 hrs later. Rapidly following injury, 5-10 fold renal cortical and isolated proximal tubule AAT mRNA and protein increases occurred. These were paralleled by rapid (>100 fold) increases in urinary AAT excretion. AKI also induced marked increases in renal cortical/isolated proximal tubule NE mRNA. However, sharp NE protein levels declines resulted, which strikingly correlated (r, -0.94) with rising AAT protein levels (reflecting NE complexing by AAT/destruction). NE addition to HK-2 cells evoked ∼95% cell death. AAT completely blocked this NE toxicity, as well as Fe induced oxidant HK-2 cell attack. Translational relevance of experimental AAT gene induction was indicated by ∼100-1000 fold urinary AAT increases in 22 AKI patients (matching urine NGAL increases). We conclude: i) AKI rapidly up-regulates the renal cortical/proximal tubule AAT gene; ii) NE gene induction also results; iii) AAT can confer cytoprotection, potentially by blocking/reducing cytotoxic NE accumulation; and iv) marked increases in urinary AAT excretion in AKI patients implies clinical relevance of the AKI- AAT induction pathway.
The Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, Washington, United States of America.
Richard A
RA
Zager
The Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, Washington, United States of America.
Ali C M
AC
Johnson
The Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, Washington, United States of America.
Kirsten B
KB
Frostad
D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D053099:Azotemia / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000737:chemistry; D051379:Mice; D010641:Phenotype; D015427:Reperfusion Injury / Q000378:metabolism; D015854:Up-Regulation; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism
D000209:Acute-Phase Proteins; D008298:Maleates; D000515:alpha 1-Antitrypsin; C030272:maleic acid; D019272:Leukocyte Elastase; D005990:Glycerol; D002945:Cisplatin