Phosphorous Dysregulation Induced by MEK Small Molecule Inhibitors in the Rat Involves Blockade of FGF-23 Signaling in the Kidney | Zendy

Dolores Diaz | Zendy; Krishna P. Allamneni | Zendy; Jacqueline M. Tarrant | Zendy; Sock-Cheng Lewin-Koh | Zendy; Rama Pai | Zendy; Preeti Dhawan | Zendy; Gary Cain | Zendy; Cleopatra Kozlowski | Zendy; Hajime Hiraragi | Zendy; Nghi La | Zendy; Dylan P. Hartley | Zendy; Xiao Ding | Zendy; B.J. Dean | Zendy; Sheila Bheddah | Zendy; Donna M. Dambach | Zendy

Open Access

Phosphorous Dysregulation Induced by MEK Small Molecule Inhibitors in the Rat Involves Blockade of FGF-23 Signaling in the Kidney

Author(s) -

Dolores Diaz,

Krishna P. Allamneni,

Jacqueline M. Tarrant,

Sock-Cheng Lewin-Koh,

Rama Pai,

Preeti Dhawan,

Gary Cain,

Cleopatra Kozlowski,

Hajime Hiraragi,

Nghi La,

Dylan P. Hartley,

Xiao Ding,

B.J. Dean,

Sheila Bheddah,

Donna M. Dambach

Publication year - 2011

Publication title -

toxicological sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.352

H-Index - 183

eISSN - 1096-6080

pISSN - 1096-0929

DOI - 10.1093/toxsci/kfr263

Subject(s) - blockade , fibroblast growth factor , small molecule , kidney , chemistry , signal transduction , cancer research , microbiology and biotechnology , pharmacology , medicine , endocrinology , biology , biochemistry , receptor

MEK, a kinase downstream of Ras and Raf oncogenes, constitutes a high priority target in oncology research. MEK small molecule inhibitors cause soft tissue mineralization in rats secondary to serum inorganic phosphorus (iP) elevation, but the molecular mechanism for this toxicity remains undetermined. We performed investigative studies with structurally distinct MEK inhibitors GEN-A and PD325901 (PD-901) in Sprague-Dawley rats. Our data support a mechanism that involves FGF-23 signal blockade in the rat kidney, causing transcriptional upregulation of 25-hydroxyvitamin D(3) 1-alpha-hydroxylase (Cyp27b1), the rate-limiting enzyme in vitamin D activation, and downregulation of 1,25-dihydroxyvitamin D(3) 24-hydroxylase (Cyp24a1), the enzyme that initiates the degradation of the active form of vitamin D. These transcriptional changes increase serum vitamin D levels, which in turn drive the increase in serum iP, leading to soft tissue mineralization in the rat.

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