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Mitogen-Activated Protein Kinase Phosphorylation in Kidneys of ß^s Sickle Cell Mice

MILITZA KIROYCHEVA^*, FAYYAZ AHMED^*, GILLIAN M. ANTHONY^*, CSABA SZABO, GARRY J. SOUTHAN and NORMAN BANK^*

^* Renal Division, Department of Medicine, Montefiore Medical Center, Bronx, New York
Inotek, Inc., Beverly, Massachusetts.

Correspondence to Dr. Norman Bank, Renal Division, Montefiore Medical Center, 111 East 210 Street, Bronx, NY 10467. Phone: 718-920-4991; Fax: 718-920-6658; E-mail: nbankmd{at}aol.com

Abstract. Previous studies in ß^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 ß^s versus normal mice. To determine whether nitration of tyrosine by ONOO^- was responsible for reduced phosphorylation of p38 and ERK, mercaptoethylguanidine (MEG), a compound known to reduce inducible isoform of nitric oxide synthase activity and to scavenge ONOO^-, was administered to ß^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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673