maleic-acid and Ureteral-Obstruction

This study evaluated the potential utility of albuminuria as a "biomarker" of acute kidney injury (AKI) and tested whether AKI induces renal expression of the normally silent albumin gene. Urine albumin concentrations were measured in mice with five different AKI models (maleate, ischemia-reperfusion, rhabdomyolysis, endotoxemia, ureteral obstruction). Albumin gene induction in renal cortex, and in antimycin A-injured cultured proximal tubular cells, was assessed (mRNA levels; RNA polymerase II binding to the albumin gene). Albumin's clinical performance as an AKI biomarker was also tested (29 APACHE II-matched intensive care unit patients with and without AKI). Results were contrasted to those obtained for neutrophil gelatinase-associated lipocalin (NGAL), an established "AKI biomarker" gene. The experimental and clinical assessments indicated albumin's equivalence to NGAL as an AKI biomarker (greater specificity in experimental AKI; slightly better receiver-operating curve in humans). Furthermore, experimental AKI markedly induced the albumin gene (mRNA/RNA polymerase II binding increases; comparable to those seen for NGAL). Albumin gene activation in patients with AKI was suggested by fivefold increases in RNA polymerase II binding to urinary fragments of the albumin gene (vs. AKI controls). Experimental AKI also increased renal cortical mRNA levels for α-fetoprotein (albumin's embryonic equivalent). A correlate in patients was increased urinary α-fetoprotein excretion. We conclude that AKI can unmask, in the kidney, the normally silent renal albumin and α-fetoprotein genes. In addition, the urinary protein data independently indicate that albuminuria, and perhaps α-fetoprotein, have substantial utility as biomarkers of acute tubular injury.

Topics: Acute Kidney Injury; Adult; Aged; Albumins; Albuminuria; Animals; Biomarkers; Cells, Cultured; Endotoxemia; Female; Glycerol; Humans; Kidney Cortex; Kidney Tubules, Proximal; Male; Maleates; Mice; Mice, Inbred Strains; Middle Aged; Models, Animal; Reperfusion Injury; Rhabdomyolysis; Severity of Illness Index; Ureteral Obstruction

Acute renal failure (ARF) sensitizes the kidney to endotoxin (LPS)-driven production of cytokines and chemokines. This study assessed whether this LPS hyperresponsiveness exists at the genomic level. Three heterogeneous mouse models of ARF were studied: Maleate nephrotoxicity, unilateral ureteral obstruction, and LPS preconditioning. In all cases, LPS was injected approximately 18 h after injury was induced, and over the next 0 to 90 min, RNA polymerase II recruitment to the genome at three LPS-responsive genes (TNF-alpha, monocyte chemoattractant-1 [MCP-1], and heme oxygenase-1 [HO-1]) was assessed by chromatin immunoprecipitation. LPS hyperresponsiveness was noted in each model, measured by exaggerated increases in TNF-alpha and MCP-1 mRNA (approximately two to 10 times higher than LPS-injected controls). Corresponding increases in the recruitment of RNA polymerase II to the TNF-alpha and MCP-1 genes were observed, and increased trimethylation of histone 3 lysine 4 (H3K4m3) at these sites may have played a role in this recruitment. Conversely, recruitment of RNA polymerase II to the HO-1 gene was suppressed ("tolerance"), and no increase in H3K4m3 was observed at HO-1 exons. The ARF-induced changes in mRNA did not correlate with mRNA stability, suggesting the mechanistic importance of RNA polymerase II-mediated transcriptional events. In conclusion, LPS hyperresponsiveness after ARF is likely mediated at the genomic level, possibly by H3K4m3.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Chemokine CCL2; Exons; Genes, rRNA; Heme Oxygenase-1; Histones; Kidney Cortex; Kidney Tubules, Proximal; Lipopolysaccharides; Lysine; Maleates; Mice; RNA Polymerase II; RNA, Messenger; Transcription, Genetic; Tumor Necrosis Factor-alpha; Ureteral Obstruction