Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury

• Published in: PloS one Vol. 9; no. 5; p. e98380
• Main Authors: Zager, Richard A, Johnson, Ali C M, Frostad, Kirsten B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21-05-2014; Public Library of Science (PLoS)
• Subjects: AAT gene; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - urine; Acute-Phase Proteins - metabolism; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; Animals; Apoptosis; Azotemia - metabolism; Biology and Life Sciences; Biomarkers; Cancer; Cell death; Cell Line; Cisplatin; Cisplatin - chemistry; Cytotoxicity; Elastase; Excretion; Gene expression; Genes; Glycerol; Glycerol - chemistry; Humans; Injuries; Ischemia; Kidney - metabolism; Kidney Cortex - metabolism; Kidney Tubules - metabolism; Kidney Tubules, Proximal - metabolism; Kidneys; Leukocyte Elastase - metabolism; Male; Maleates - chemistry; Medical research; Medicine and Health Sciences; Mice; mRNA; Neutrophils; Patients; Phenotype; Phenotypes; Protease; Protease inhibitors; Proteases; Protein folding; Proteinase inhibitors; Proteins; Reperfusion Injury - metabolism; RNA; RNA polymerase; Rodents; Toxicity; Up-Regulation; Urine; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0098380

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.