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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Pittock
Siobhan T
ST
Department of Pediatric and Adolescent Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
Norby
Suzanne M
SM
Grande
Joseph P
JP
Croatt
Anthony J
AJ
Bren
Gary D
GD
Badley
Andrew D
AD
Caplice
Noel M
NM
Griffin
Matthew D
MD
Nath
Karl A
KA
D000367:Age Factors; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006454:Hemoglobins / Q000633:toxicity; D007511:Ischemia / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D013312:Stress, Physiological / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D015996:Survival Rate; D015854:Up-Regulation
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006454:Hemoglobins; D008565:Membrane Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse