Isozymes of heme oxygenase (HO) convert heme to biliverdin and provide the dominant heme-degradative mechanisms in tissues. HO-1 is the inducible, while HO-2 is the constitutive, isoform; HO-3 possesses trivial heme-degrading activity. The study of HO attracts considerable interest because of the recognized protective and vasorelaxant actions of HO in general, and the ready inducibility of HO-1, in particular. This R0-1 competitive renewal continues the study of HO-1 as a protective response against renal injury and pursues findings made in the present cycle: a novel stimulus for HO-1 was identified in the kidney, and one with critical relevance to renal vasoconstriction, namely, angiotensin II. Additionally, two novel pathways that may contribute to the cytoprotective actions of HO-1 were uncovered: the suppressive effect of HO-1 on monocyte chemoattractant protein-1 (MCP- 1), a chemokine incriminated in renal inflammation, and the inductive effect of HO-1 on p21Cip1.WAF1.SDII a cyclin-dependent kinase inhibitor which is also anti-apoptotic. Thus, induction of HO-1, on the one hand, may vitiate pathways of renal injury (angiotensin IT-induced vasoconstriction, the upregulation of MCP-1), while, on the other, HO-I induction may recruit p21-dependent pathways of protection. Because of the importance of angiotensin II, MCP-l, and p21 as determinants of renal injury, our renewal application pursues three specific aims.
Aim I hypothesizes that the HO system is a countervailing one that opposes the systemic and renal vasoconstrictive actions of angiotensin II; studies in this aim alter the expression of the HO system by pharmacologic, antisense approaches, and gene delivery, and examine their effects on angiotensin TI-induced constriction.
Aim II hypothesizes that the HO system suppresses renal expression of MCP-1. Using in vitro and in vivo models for lipopolysaccharide-induced MCP-l expression, this aim examines the regulatory role of the HO system on MCP-1 expression, focusing on the redox-regulatory effect of HO on NF-kB, the latter transcription factor critically controlling MCP-1 expression.
Aim III hypothesizes that the HO system upregulates p21 which contributes to the protective actions of HO-1.
This aim delineates the role of the cell cycle-inhibitory, anti-apoptotic molecule, p21, as a transducer of the cytoprotective effects of HO-1. Our proposals thus explore mechanisms by which HO interrupts major pathways of injury (Aims I and II) as well as recruits pathways that safeguard the kidney (Aim III).
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