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American Journal of Pathology, Vol 150, 603-615, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Immunological evidence for hypochlorite-modified proteins in human kidney

E Malle, C Woenckhaus, G Waeg, H Esterbauer, EF Grone and HJ Grone
Karl-Franzens University Graz, Germany.

Oxygen radicals and oxidatively modified proteins seem to participate in degenerative vascular and inflammatory diseases. Factors that contribute to the development of atherosclerosis, eg, oxidation of low- density lipoproteins (LDLs), may also contribute to glomerulosclerosis. Although the nature of the in vivo oxidants remains unknown, recent findings indicated that the myeloperoxidase (MPO)-H2O2-halide system could play an important role in modification of (lipo)proteins in human tissues. MPO, the enzyme responsible for hypochlorite (HOCl/OCl-) formation, is present in human atherosclerotic lesions and in inflammatory conditions. In the present study, MPO was identified by Western blot analysis and immunohistochemical technique in diseased human kidney either with primarily sclerotic or inflammatory lesions. Furthermore, the presence of HOCl-modified proteins was demonstrated in diseased renal tissues using a specific monoclonal antibody (clone 2D10G9), raised against HOCl-modified LDL, that does not cross-react with native LDL or Cu(2+)-, 4-hydroxynonenal-, or malondialdehyde- modified LDL. The antibody recognized HOCl-modified proteins in glomerular and tubulointerstitial inflammatory and fibrotic lesions and pronounced immunostaining was demonstrated in mononuclear cells. LDL or human serum albumin oxidized by HOCl in vitro, but not native LDL or human serum albumin, effectively competed with epitopes in diseased kidney for antibody binding. Western blot analysis in diseased kidney protein samples revealed at least two major proteins recognized by the anti-HOCl-modified protein monoclonal antibody. Densitometric evaluation of immunoreactive bands obtained under these conditions demonstrated that expression of HOCl-modified proteins is tightly coupled to expression of immunoreactive MPO in the same tissue samples. From our studies it is proposed that oxidation of proteins by HOCl might be a leading event in glomerular and tubulointerstitial injury. By this mechanism, mononuclear cells, a permanent source for MPO, may play a key role in the development of nephrosclerosis, glomerulo- clerosis, and tubulointerstitial fibrosis, respectively.

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