RENAL INJURY AND ADAPTATION TO HEME PROTEINS

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Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme. HO thus reduces cellular levels of heme, a pro-oxidant, and ultimately procures bilirubin, an antioxidant. HO exists as an oxidant and cytokine-inducible isoform, HO-1, and an unresponsive constitutive isoform, HO-2, We demonstrate that induction of HO-1 protects against oxidant injury imposed by heme proteins and other toxins. These effects of HO-1 are contingent upon synthesis of ferritin (the major intracellular iron-binding protein), and possibly, induction of Heme Binding Protein 23 (an inducible high affinity heme binding protein); this integrated response limits the cytotoxicity of oxidants and cytokines incurred as intracellular heme proteins are destabilized and heme is released. We recently observed that HO-1 is upregulated in renal inflammation and reduces susceptibility to subsequent insults. That HO-1 is involved in inflammation and is a determinant if tissue injury thus carries this enzyme beyond toxic nephropathies into areas with timely and far-reaching biologic appeal. We propose 4 specific aims. The first specific aim is the development of transgrenic models that overexpress HO-1 and ferritin, globally, as well as regionally in the kidney; this approach complements pharmacologic studies. We will test whether such animals are less susceptible to toxic and inflammatory insults wherein we have obtained evidence for a protective role for HO-1 and ferritin. The second specific aim will examine induction of HO-1 and its allied molecules as determinants of resistance to oxidant injury. Oxidant injury represents a critical mechanism common to toxic and inflammatory states, and we will analyze functional significance of such induction in states of resistance to oxidative injury. The third specific aim will examine the mechanisms and significance underlying the induction of HO-1 we have observed in renal tubules in acute glomerular inflammation, nephrotoxic serum nephritis; in this TNFalpha-dependent model, HO-1 is induced in tubules and protects against renal injury. The fourth specific aim will examine the mechanisms and significance of induction of HO-1 in macrophages in acute interstitial inflammation. Macrophages are critical components in renal injury in general and in allograft rejection in particular. In our characterized model of acute allograft rejection we will pursue the mechanisms and significance of induction of HO-1 in interstitial macrophages. Our proposed application thus continues to pursue the functionality of HO-1, as it utilized a new strategy, transgenic mice, and as it defines a new area of involvement namely, renal inflammation.