Heme oxygenase (HO) converts heme to biliverdin during which iron is released and carbon monoxide (CO) is emitted;biliverdin reductase subsequently converts biliverdin to bilirubin. In 1992, the Pi'slaboratory provided the first evidence that HO-1 was cytoprotective, a finding derived in acute renal heme-mediated injury, and which was the basis for the 1993-1997 funding cycle;the 1997-2002 cycle was based on the finding by the Pi's laboratory that HO-1 was cytoprotective in other forms of renal injury. The 2002-2007 cycle sought to identify pathogenetic pathways interrupted by HO-1, and demonstrated, along with relevant mechanistic insights, that the HO system inhibits: i) vasoconstriction/ischemia, li) inflammation, and iii) apoptosis. The proposed aims continue these investigative themes.
Aim I will delineate the role of the HO system in militating against vasoconstriction by examining the systemic and renal hemodynamic effects of Ang ll-dependent and Ang ll-independent vasoconstriction (theDOCA model) in HO-1""""""""'"""""""" and HO^"""""""" mice.
This aim will examine such mechanisms as NADPH oxidase, superoxide anion generation, BH4/BH2 levels and coupling of eNOS, and the role of endothelin-1;
this aim will also determine the extent to which products of HO can reverse the enhanced vasoconstriction when HO-1 or HO-2 is deficient.
Aim II will determine the basis for the anti-inflammatory effect of the HO system against LPS-induced_inflammation, targeting activation of NF-KB as a critical locus for the anti-inflammatory effects of HO. These studies will determine the following: the extent to which HO-1 regulates inflammatory responses by altering activation of NF-KB;the contribution of specific NF-KB-dependent cytokines (MCP-1, IL-6,IL-12(p40), and TNF) to the exaggerated inflammation due to HO-1 deficiency;the anti-inflammatory capacity of specific HO products and whether such products influence NF-KB activation;and finally, the capacity of HO-1 overexpression to inhibit LPS- driven inflammation.
Aim III will examine the basis for apoptosis, acute renal injury, and increased mortality in HO-1""""""""'"""""""" mice, subjected to renal ischemia, focusing on IL-6 and its signaling species, pSTAT3rthe .latter now identified as proapoptotic in the kidney. IL-6is markedly and uniquely induced in the kidney, Iung7 arid heart, and increased in the serum. In this model of apoptosis, the effect of inhibiting IL-6/pSTAT3 will Jbe determined.
This aim will also determine th$ source of IL-6 in the kidney and systemic circulation, arid the regulation of IL-6expression by HO-1.
This aim will thus determine the contribution of IL-6^'STAT-3^ apoptosis and other adverse effects of ischemia in the absence of HO-1, and the reciprocating effects between cellular expression and signaling of IL-6and HO-1. Lav Summary. This application seeks to understand how a protein called heme oxygenase-1 protects the kidney against different types of diseases. This understanding may facilitate the development of new therapies for kidney disease.
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