MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates

• Published in: Kidney international Vol. 68; no. 2; pp. 611 - 622
• Main Authors: PITTOCK, Siobhan T, NORBY, Suzanne M, GRANDE, Joseph P, CROATT, Anthony J, BREN, Gary D, BADLEY, Andrew D, CAPLICE, Noel M, GRIFFIN, Matthew D, NATH, Karl A
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-08-2005
• Subjects: Age Factors; Animals; Biological and medical sciences; Chemokine CCL2 - genetics; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase-1; Hemoglobins - toxicity; Ischemia - mortality; Ischemia - pathology; Ischemia - physiopathology; Kidney Diseases - mortality; Kidney Diseases - pathology; Kidney Diseases - physiopathology; Kidney Glomerulus - pathology; Kidney Glomerulus - physiopathology; Medical sciences; Membrane Proteins; Mice; Mice, Knockout; Nephrology. Urinary tract diseases; Stress, Physiological - mortality; Stress, Physiological - pathology; Stress, Physiological - physiopathology; Survival Rate; Up-Regulation; Nephrology; Pathophysiology; cytoprotection; Enzyme; Heme oxygenase (decyclizing); monocyte chemoattractant protein-1; Cardiovascular disease; heme oxygenase-1; Kidney; Stress; Urology; Chemokine; Regulation(control); Urinary system; Ischemia; Animal; Knockout mouse; Oxidoreductases; Monocyte chemoattractant protein 1
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1111/j.1523-1755.2005.00439.x

Up-regulation of heme oxygenase-1 (HO-1) occurs in, and often confers protection to, the injured kidney. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) promotes not only acute and chronic nephritides but also acute ischemic and nephrotoxic injury. The present study was stimulated by the hypothesis that expression of MCP-1 is suppressed by HO-1, and analyzed the effect of HO-1 on the expression of MCP-1 in stressed and unstressed conditions.
Expression of MCP-1 and pathophysiologic correlates were examined in HO-1 knockout (HO-1-/-) and wild-type (HO-1+/+) mice in the unstressed state in young and aged mice, and following nephrotoxic and ischemic insults.
In unstressed HO-1-/- mice, plasma levels of MCP-1 protein were elevated, and MCP-1 mRNA expression was increased in circulating leukocytes and in the kidney. Such early and heightened up-regulation of MCP-1 was eventually accompanied by phenotypic changes in the aged kidney consistent with MCP-1, namely, proliferative changes in glomeruli, tubulointerstitial disease, and up-regulation of transforming growth factor-beta1 (TGF-beta1) and collagens I, III, and IV. In response to a nephrotoxic insult such as hemoglobin, MCP-1 mRNA was up-regulated in a markedly sustained manner in HO-1-/- mice. In response to a duration of ischemia that exerted little effect in HO-1+/+ mice, HO-1-/- mice exhibited higher expression of MCP-1 mRNA, enhanced activation of nuclear factor-kappaB (NF-kappaB) (the transcription factor that regulates MCP-1), markedly greater functional and structural renal injury, increased caspase-3 expression, and increased mortality.
In the absence of HO-1, expression of MCP-1 is significantly and consistently enhanced in unstressed and stressed conditions. We speculate that the protective effects of HO-1 in injured tissue may involve, at least in part, the capacity of HO-1 to restrain up-regulation of MCP-1.