title: Sequential expression of NKCC2, TonEBP, aldose reductase, and urea transporter-A in developing mouse kidney.
abstract: This study was conducted to test the hypothesis that, during renal development, the Na-K-2Cl cotransporter type 2 (NKCC2) activates the tonicity-responsive enhancer binding protein (TonEBP) transcription factor by creating medullary hypertonicity. TonEBP, in turn, drives the expression of aldose reductase (AR) and urea transporter-A (UT-A). Kidneys from 13- to19-day-old fetuses (F13-F19), 1- to 21-day-old pups (P1-P21), and adult mice were examined by immunohistochemistry. NKCC2 was first detected on F14 in differentiating macula densa and thick ascending limb (TAL). TonEBP was first detected on F15 in the medullary collecting duct (MCD) and surrounding endothelial cells. AR was detected in the MCD cells of the renal medulla from F15. UT-A first appeared in the descending thin limb (DTL) on F16 and in the MCD on F18. After birth, NKCC2-positive TALs disappeared gradually from the tip of the renal papilla, becoming completely undetectable in the inner medulla on P21. TonEBP shifted from the cytoplasm to the nucleus in both vascular endothelial cells and MCD cells on P1, and its abundance increased gradually afterward. Immunoreactivity for AR and UT-A in the renal medulla increased markedly after birth. Treatment of neonatal animals with furosemide dramatically reduced expression of TonEBP, AR, and UT-A1. Furosemide also prevented the disappearance of NKCC2-expressing TALs in the papilla. The sequential expression of NKCC2, TonEBP, and its targets AR and UT-A and the reduced expression TonEBP and its targets in response to furosemide treatment support the hypothesis that local hypertonicity produced by the activity of NKCC2 activates TonEBP during development.
authors.affiliation: Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul.
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Lee
authors.forename: Wan-Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Hyun-Kuk
authors.initials: HK
authors.lastname: Song
authors.forename: Chul-Woo
authors.initials: CW
authors.lastname: Yang
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Han
authors.forename: H Moo
authors.initials: HM
authors.lastname: Kwon
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
mesh_terms: D000449:Aldehyde Reductase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000033:anatomy & histology / Q000254:growth & development* / Q000378:metabolism*; D007679:Kidney Medulla / Q000378:metabolism / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis* / Q000235:genetics; D064466:Solute Carrier Family 12, Member 1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014867:Water / Q000378:metabolism; D000096982:Urea Transporters
chemical_list: D000449:Aldehyde Reductase; D004232:Diuretics; D005665:Furosemide; D026901:Membrane Transport Proteins; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014157:Transcription Factors; D014867:Water; D000096982:Urea Transporters; C492200:Nfat5 protein, mouse; C578715:Slc12a1 protein, mouse