MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates1

Pittock, Siobhán; Norby, Suzanne M.; Grande, Joseph P.; Croatt, Anthony J.; Bren, Gary D.; Badley, Andrew D.; Caplice, Noel M.; Griffin, Matthew D.; Nath, Karl A.

doi:10.1111/j.1523-1755.2005.00439.x

Cited by 102 publications

(130 citation statements)

References 46 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…40 In addition, it was demonstrated that whereas basal MCP-1 expression in some tissues, such as heart and bone marrow, was comparable in both HO-1 ϩ/ϩ and HO-1 Ϫ/Ϫ mice, renal and plasma MCP-1 were elevated in unstressed and stressed HO-1 Ϫ/Ϫ mice. 41 In this study, the number of macrophages in the kidneys from the sham-operated group and the CL (right) kidneys did not differ between the two HO-1 genotypes but was significantly higher in the obstructed kidneys of HO-1 Ϫ/Ϫ mice. Interestingly, the amount BASIC RESEARCH www.jasn.org of fibrosis seemed to affect the CL kidneys from HO-1 Ϫ/Ϫ mice more than in the respective kidneys from HO-1 ϩ/ϩ mice, with a trend toward statistical significance (P ϭ 0.07), suggesting a systemic effect of the inflammatory process, perhaps caused by differences in resident and circulating cytokines.…”

Section: Discussionmentioning

confidence: 84%

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Kie

Kapturczak

Traylor

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Induction of heme oxygenase-1 (HO-1) is associated with potential antifibrogenic effects. The effects of HO-1 expression on epithelial-mesenchymal transition (EMT), which plays a critical role in the development of renal fibrosis, are unknown. In this study, HO-1 Ϫ/Ϫ mice demonstrated significantly more fibrosis after 7 d of unilateral ureteral obstruction compared with wild-type mice, despite similar degrees of hydronephrosis. The obstructed kidneys of HO-1 Ϫ/Ϫ mice also had greater macrophage infiltration and renal tubular TGF-␤1 expression than wild-type mice. In addition, the degree of EMT was more extensive in obstructed HO-1 Ϫ/Ϫ kidneys, as assessed by ␣-smooth muscle actin and expression of S100A4 in proximal tubular epithelial cells. In vitro studies using proximal tubular cells isolated from HO-1 Ϫ/Ϫ and wild-type kidneys confirmed these observations. In conclusion, HO-1 deficiency is associated with increased fibrosis, tubular TGF-␤1 expression, inflammation, and enhanced EMT in obstructive kidney disease. Modulation of the HO-1 pathway may provide a new therapeutic approach to progressive renal diseases.

show abstract

Section: Discussionmentioning

confidence: 84%

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Kie

Kapturczak

Traylor

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Sustained increases in their levels have been associated with persistent inflammation, neovascularization, and decreased re-epithelialization and tissue repair. 44 -47 The fact that these same chemokines are subjected to down-regulation by either HO-1 induction or supplementation of CO or biliverdin, 21,43,48,49 further underscores the notion that the absence of considerable HO activity promoted the uncontrolled massive production of proinflammatory signals and, consequently, chronic inflammation and neovascularization. This is strongly supported by the demonstration that biliverdin administration rescued the impaired inflammatory and reparative response of the HO-2-null mice; it accelerated wound repair, promoted resolution, and attenuated neovascularization.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Seta

Bellner

Rezzani

et al. 2006

The American Journal of Pathology

120

View full text Add to dashboard Cite

Heme oxygenase (HO) represents an intrinsic antiinflammatory system based on its ability to regulate leukocyte function and inhibit expression of proinflammatory cytokines. This anti-inflammatory function is linked to the inducible isoform HO-1; the role of the constitutive isoform HO-2 is unknown. The current study was undertaken to investigate the role of HO-2 in the regulation of the acute inflammatory and reparative response by using HO-2-null mice and well-established animal models of epithelial injury and antigen-induced peritonitis. Here we show that in vivo deletion of HO-2 disables execution of the acute inflammatory and reparative response after epithelial injury and leads to an exaggerated inflammatory response in antigen-induced peritonitis. HO-2 deletion was associated with impaired HO-1 induction, indicating that HO-2 is critical for HO-1 expression and that the subsequent failure to up-regulate the HO system may contribute to unresolved inflammation and the development of chronic inflammatory conditions. Indeed, supplementation with the HO bioactive product, biliverdin, rescued the acute inflammatory and reparative response in HO-2-null mice. Thus, HO-2 sets in place a basal tone of anti-inflammatory signals that may be a prerequisite for the ordered execution of an inflammatory and reparative response.

show abstract

“…HO-1's downregulation may be due to the glucose effect on HO-1 promoter activity (59) and may cause renal dysfunction (for review, see [40]). HO-1 upregulation decreases inflammatory cytokines (60,61). Bilirubin can scavenge reactive oxygen species (62)(63)(64) and inhibit activation of NADPH oxidase (15) and protein kinase C (16), which are key signaling steps in oxidant-induced vascular injury.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (؉/؉) mice and HO-2 knockout (؊/؊) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (؊/؊) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (؉/؉). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (؊/؊) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (؊/؊) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (؊/؊) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

show abstract

MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates1

Abstract: 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.

Cited by 102 publications

References 46 publications

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Contact Info

Product

Resources

About