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Am J Physiol Renal Physiol (April 8, 2003). doi:10.1152/ajprenal.00422.2002
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Submitted on December 11, 2002
Accepted on April 4, 2003

pH-responsive Stabilization of Glutamate Dehydrogenase mRNA in LLC-PK1-F+ cells

Jill M. Schroeder1, Wenlin Liu1, and Norman P. Curthoys1*

1 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA

* To whom correspondence should be addressed. E-mail: Norman.Curthoys{at}Colostate.ed.

During chronic metabolic acidosis, the adaptive increase in rat renal ammoniagenesis is sustained, in part, by increased expression of the mitochondrial glutaminase (GA) and glutamate dehydrogenase (GDH) enzymes. The increase in GA activity results from the pH-responsive stabilization of the GA mRNA. The 3'-untranslated region (3'-UTR) of the GA mRNA contains a direct repeat of an 8-base AU-rich element (ARE) that binds {zeta}-crystallin/NADPH:quinone reductase ({zeta}-crystallin) with high affinity and functions as a pH-response element (pHRE). RNA electrophoretic mobility shift assays (EMSA) established that {zeta}-crystallin also binds to the full-length 3'-UTR of the GDH mRNA. This region contains four 8-base sequence that are 88% identical to one of the two GA AREs. Direct binding assays and competition studies indicate that the two individual 8-base AREs from the GA mRNA and the four individual GDH sequences bind {zeta}-crystallin with different affinities. Insertion of the 3'-UTR of the GDH cDNA into a {beta}-globin expression vector (p{beta}G) produced a chimeric mRNA that was stabilized when LLC-PK1-F+ cells were transferred to acidic medium. A pH-responsive stabilization was also observed using a {beta}G construct that contained only the single GDH4 ARE and a destabilizing element from the PEPCK mRNA. Therefore during acidosis, the pH-responsive stabilization of the GDH mRNA may be accomplished by the same mechanism that affects an increase in the GA mRNA.




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