Mice lacking mPGES-1 are resistant to lithium-induced polyuria.
Cyclooxygenase-2 activity is required for the development of lithium-induced polyuria. However, the involvement of a specific, terminal prostaglandin (PG) isomerase has not been evaluated. The present study was undertaken to assess lithium-induced polyuria in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1). A 2-wk administration of LiCl (4 mmol.kg(-1).day(-1) ip) in mPGES-1 +/+ mice led to a marked polyuria with hyposmotic urine. This was associated with elevated renal mPGES-1 protein expression and increased urine PGE(2) excretion. In contrast, mPGES-1 -/- mice were largely resistant to lithium-induced polyuria and a urine concentrating defect, accompanied by nearly complete blockade of high urine PGE(2) and cAMP output. Immunoblotting, immunohistochemistry, and quantitative (q) RT-PCR consistently detected a significant decrease in aquaporin-2 (AQP2) protein expression in both the renal cortex and medulla of lithium-treated +/+ mice. This decrease was significantly attenuated in the -/- mice. qRT-PCR detected similar patterns of changes in AQP2 mRNA in the medulla but not in the cortex. Similarly, the total protein abundance of the Na-K-2Cl cotransporter (NKCC2) in the medulla but not in the cortex of the +/+ mice was significantly reduced by lithium treatment. In contrast, the dowregulation of renal medullary NKCC2 expression was significantly attenuated in the -/- mice. We conclude that mPGES-1-derived PGE(2) mediates lithium-induced polyuria likely via inhibition of AQP2 and NKCC2 expression.
Jia
Zhanjun
Z
Univ. of Utah and VA Medical Center, Salt Lake City, UT 84132, USA.
Wang
Haiping
H
Yang
Tianxin
T
D000818:Animals; D051399:Aquaporin 2 / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism / Q000652:urine; D004198:Disease Susceptibility; D015536:Down-Regulation; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007671:Kidney Concentrating Ability / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011141:Polyuria / Q000139:chemically induced*; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency* / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1
D051399:Aquaporin 2; D002352:Carrier Proteins; C578715:Slc12a1 protein, mouse; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D008094:Lithium; D011451:Prostaglandin-Endoperoxide Synthases; D000071876:Prostaglandin-E Synthases; C497818:Ptges protein, rat; D015232:Dinoprostone
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