Mitogen-activated protein kinase phosphorylation in kidneys of β(s) sickle cell mice

Militza Kiroycheva, Fayyaz Ahmed, Gillian M. Anthony, Csaba Szabo, Garry J. Southan, Norman Bank

Research output: Contribution to journalArticle

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Abstract

Previous studies in β(s) sickle cell mice demonstrated renal immunostaining for nitrotyrosine, which is putative evidence of peroxynitrite (ONOO-) formation. ONOO- is known to nitrate tyrosine residues of various enzymes, thereby interfering with phosphorylation and inactivating them. The present study examined the state of phosphorylation of mitogen-activated protein (MAP) kinase signal transduction enzymes, i.e., p38, c-Jun NH2- terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Western blot performed with antibodies directed against specific phosphorylated threonine/tyrosine residues of these enzymes demonstrated reduced phosphorylation of renal p38 and a trend toward reduced phosphorylation of ERK. In contrast, phosphorylation of renal JNK was markedly increased compared with normal mice. The abundance of MAP kinase phosphatase-1 (MKP-1), a key upstream enzyme that modulates phosphorylation of MAP kinases, was not different in β(s) versus normal mice. To determine whether nitration of tyrosine by ONOO- was responsible for reduced phosphorylation of p38 and ERK, mercaptoethyl-guanidine (MEG), a compound known to reduce inducible isoform of nitric oxide synthase activity and to scavenge ONOO-, was administered to β(s) mice for 5 d. MEG was found to restore phosphorylation of p38 and ERK toward normal levels. These observations provide evidence that ONOO- (or closely related reaction products of NO) contributes to dephosphorylation of p38 and ERK, and presumably reduces activity of these enzymes. The increased phosphorylation of JNK, which suggests activation of this signaling pathway by extracellular stress signals, may play a role in apoptosis in the kidneys of these mice. The changes in phosphorylation of MAP kinase pathways found in this study could have important consequences for regulation of nuclear transcription factors, and thus renal function and pathology in sickle cell kidneys.

Original languageEnglish (US)
Pages (from-to)1026-1032
Number of pages7
JournalJournal of the American Society of Nephrology
Volume11
Issue number6
StatePublished - Jun 2000
Externally publishedYes

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Mitogen-Activated Protein Kinases
Phosphorylation
Kidney
Extracellular Signal-Regulated MAP Kinases
Tyrosine
Enzymes
Guanidine
Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
Peroxynitrous Acid
JNK Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type II
Threonine
Nitrates
Signal Transduction
Protein Isoforms
Transcription Factors
Western Blotting
Apoptosis
Pathology

ASJC Scopus subject areas

  • Nephrology

Cite this

Kiroycheva, M., Ahmed, F., Anthony, G. M., Szabo, C., Southan, G. J., & Bank, N. (2000). Mitogen-activated protein kinase phosphorylation in kidneys of β(s) sickle cell mice. Journal of the American Society of Nephrology, 11(6), 1026-1032.

Mitogen-activated protein kinase phosphorylation in kidneys of β(s) sickle cell mice. / Kiroycheva, Militza; Ahmed, Fayyaz; Anthony, Gillian M.; Szabo, Csaba; Southan, Garry J.; Bank, Norman.

In: Journal of the American Society of Nephrology, Vol. 11, No. 6, 06.2000, p. 1026-1032.

Research output: Contribution to journalArticle

Kiroycheva, M, Ahmed, F, Anthony, GM, Szabo, C, Southan, GJ & Bank, N 2000, 'Mitogen-activated protein kinase phosphorylation in kidneys of β(s) sickle cell mice', Journal of the American Society of Nephrology, vol. 11, no. 6, pp. 1026-1032.
Kiroycheva M, Ahmed F, Anthony GM, Szabo C, Southan GJ, Bank N. Mitogen-activated protein kinase phosphorylation in kidneys of β(s) sickle cell mice. Journal of the American Society of Nephrology. 2000 Jun;11(6):1026-1032.
Kiroycheva, Militza ; Ahmed, Fayyaz ; Anthony, Gillian M. ; Szabo, Csaba ; Southan, Garry J. ; Bank, Norman. / Mitogen-activated protein kinase phosphorylation in kidneys of β(s) sickle cell mice. In: Journal of the American Society of Nephrology. 2000 ; Vol. 11, No. 6. pp. 1026-1032.
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