Renal Injury and Adaptation to Heme Proteins

Project: Research project

Project Details


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.
StatusNot started


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