Heme protein-mediated renal injury: A protective role for 21-aminosteroids in vitro and in vivo

Karl A Nath, J. Balla, A. J. Croatt, G. M. Vercellotti

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

21-aminosteroids ('lazaroids') have recently excited much interest by virtue of their ability to inhibit lipid peroxidation in vitro and to protect against neural injury in vivo. We tested the effect of these compounds in models of heme protein-mediated renal injury in vitro and in vivo. We devised an in vitro model of heme protein-induced toxicity in which renal epithelial cells were exposed to heme proteins for one hour, after which they were subjected to glutathione depletion by 1-chloro-2,4 dinitrobenzene (CDNB). This model was associated with more than a threefold increase in lipid peroxidation (as measured by thiobarbituric acid reactive substances, TBARS) and a marked reduction in cellular glutathione content. In this model, 21-aminosteroids virtually prevented cytotoxicity as measured by the 51-chromium release assay, and significantly reduced TBARS in a dose-dependent manner. Catalase was partially protective in this model, thereby indicating hydrogen peroxide-dependent toxicity. While pursuing mechanisms accounting for enhanced cellular generation of hydrogen peroxide, we uncovered the first direct evidence that the heme prosthetic group per se directly stimulates cellular generation of hydrogen peroxide; complementing these findings is the remarkable efficacy of 21-aminosteroids in protecting against cytotoxicity induced by hydrogen peroxide. We also tested the capacity of 21-aminosteroids to protect against heme protein-mediated renal injury in vivo. Prior administration of 21-aminosteroids attenuated reductions in GFR and renal blood flow rates following the systemic infusion of methemoglobin in normal rats. 21-aminosteroids also attenuated renal injury observed over three successive days in the glycerol model of heme protein-mediated injury when this model was induced at a higher dose of glycerol (8 ml/kg body wt) but not at a lower dose (5 ml/kg body wt). We conclude that 21-aminosteroids protect against beme protein-mediated renal injury in vitro and in vivo. We suggest that these compounds are potentially useful in such clinical conditions as rhabdomyolysis, intravascular hemolysis and renal injury associated with hemoglobin-based red blood cell substitutes.

Original languageEnglish (US)
Pages (from-to)592-602
Number of pages11
JournalKidney International
Volume47
Issue number2
StatePublished - 1995
Externally publishedYes

Fingerprint

Hemeproteins
Kidney
Wounds and Injuries
Hydrogen Peroxide
Blood Substitutes
Thiobarbituric Acid Reactive Substances
Glycerol
Lipid Peroxidation
Glutathione
Dinitrochlorobenzene
Methemoglobin
Rhabdomyolysis
Renal Circulation
Chromium
Hemolysis
In Vitro Techniques
Heme
Catalase
Hemoglobins
Erythrocytes

ASJC Scopus subject areas

  • Nephrology

Cite this

Heme protein-mediated renal injury : A protective role for 21-aminosteroids in vitro and in vivo. / Nath, Karl A; Balla, J.; Croatt, A. J.; Vercellotti, G. M.

In: Kidney International, Vol. 47, No. 2, 1995, p. 592-602.

Research output: Contribution to journalArticle

Nath, Karl A ; Balla, J. ; Croatt, A. J. ; Vercellotti, G. M. / Heme protein-mediated renal injury : A protective role for 21-aminosteroids in vitro and in vivo. In: Kidney International. 1995 ; Vol. 47, No. 2. pp. 592-602.
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