Uremia impacts renal inflammatory cytokine gene expression in the setting of experimental acute kidney injury

• Published in: American journal of physiology. Renal physiology Vol. 297; no. 4; pp. F961 - F970
• Main Authors: Zager, Richard A, Johnson, Ali C M, Lund, Steve
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.10.2009
• Subjects: Acute Kidney Injury - complications; Acute Kidney Injury - metabolism; Animals; Azotemia - blood; Azotemia - etiology; Cell Line; Chemokine CCL2 - metabolism; Chemokines - metabolism; Cytokines; Dialysis Solutions; DNA Polymerase II - metabolism; Gene Expression; Humans; Interleukin-10 - metabolism; Kidney diseases; Kidney Tubules, Proximal - metabolism; Lipopolysaccharides; Male; Mice; MicroRNAs - metabolism; Nephrology; Pathology; Reperfusion Injury - complications; Reperfusion Injury - metabolism; Ribonucleic acid; RNA; RNA, Messenger - metabolism; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Uremia - etiology; Uremia - metabolism; Ureteral Obstruction - complications; Ureteral Obstruction - metabolism
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00381.2009

Inflammatory cytokines are evoked by acute kidney injury (AKI) and may contribute to evolving renal disease. However, the impact of AKI-induced uremia on proinflammatory (e.g., TNF-alpha, MCP-1, TGF-beta1) and anti-inflammatory (e.g., IL-10) cytokine gene expression remains unknown. This study was undertaken to gain some initial insights into this issue. CD-1 mice were subjected to left renal ischemia-reperfusion (I/R) in the absence or presence of uremia (+/- right ureteral transection). TNF-alpha, MCP-1, TGF-beta1, and IL-10 mRNAs, cytokine protein levels, and RNA polymerase II (Pol II) recruitment to these genes were assessed. Renal cytokine mRNA levels were also contrasted with unilateral vs. bilateral renal parenchymal damage (I/R or ureteral obstruction). Potential effects of uremia on cytokine mRNAs in the absence of parenchymal renal damage [bilateral ureteral transection (BUTx)] were sought. Finally, the impact of simulated in vitro uremia (HK-2 tubular cells exposed to peritoneal dialysate from uremic vs. normal mice) on cytokine mRNA and microRNA profiles was assessed. Uremia blunted TNF-alpha, MCP-1, and TGF-beta1 mRNA increases in all three in vivo parenchymal acute renal failure models. These results were paralleled by reductions in cytokine protein levels and Pol II recruitment to their respective genes. Conversely, uremia increased IL-10 mRNA, both in the presence and absence (BUTx) of parenchymal renal damage. The uremic milieu also suppressed HK-2 cell proinflammatory cytokine mRNA levels and altered the expression of least 69 microRNAs (P < 0.0001). We conclude that both pro- and anti-inflammatory cytokine gene expressions are influenced by uremia, with a potential predilection toward an anti-inflammatory state. Changes in gene transcription (as reflected by Pol II recruitment), and possible posttranscriptional modifications (known to be induced by microRNAs), are likely involved.