Salt and acid-base metabolism in claudin-16 knockdown mice: impact for the pathophysiology of FHHNC patients.
Claudin-16 is defective in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Claudin-16 knockdown (CLDN16 KD) mice show reduced cation selectivity in the thick ascending limb. The defect leads to a collapse of the lumen-positive diffusion voltage, which drives Ca(2+) and Mg(2+) absorption. Because of the reduced tight junction permeability ratio for Na(+) over Cl(-), we proposed a backleak of NaCl into the lumen. Systemic analysis had revealed lower blood pressure and a moderately increased plasma aldosterone concentration. In this study, we measured the amiloride-sensitive equivalent short-circuit current in isolated, perfused collecting ducts and found it increased by fivefold in CLDN16 KD mice compared with wild-type (WT) mice. Amiloride treatment unmasked renal Na(+) loss in the thick ascending limb of the nephron. Under amiloride treatment, CLDN16 KD mice developed hyponatremia and the renal fractional excretion of Na(+) was twofold higher in CLDN16 KD compared with WT mice. The loss of claudin-16 also resulted in increased urinary flow, reduced HCO(3)(-) excretion, and lower urine pH. We conclude that perturbation in salt and acid-base metabolism in CLDN16 KD mice has its origin in the defective cation permselectivity of the thick ascending limb of the nephron. This study has contributed to the still incomplete understanding of the symptoms of FHHNC patients.
Himmerkus
Nina
N
Physiologisches Institut, Olshausenstrasse 40, D-24098 Kiel, Germany.
Shan
Qixian
Q
Goerke
Boeren
B
Hou
Jianghui
J
Goodenough
Daniel A
DA
Bleich
Markus
M
D000327:Adsorption; D000818:Animals; D002118:Calcium / Q000097:blood / Q000378:metabolism / Q000652:urine; D002463:Cell Membrane Permeability; D057167:Claudins; D003404:Creatinine / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics; D007684:Kidney Tubules / Q000502:physiology / Q000503:physiopathology; D008274:Magnesium / Q000097:blood / Q000378:metabolism / Q000652:urine; D008275:Magnesium Deficiency / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009397:Nephrocalcinosis / Q000235:genetics*; D009399:Nephrons / Q000502:physiology / Q000503:physiopathology; D010477:Perfusion; D012964:Sodium / Q000097:blood / Q000652:urine; D019108:Tight Junctions / Q000502:physiology
D057167:Claudins; D008565:Membrane Proteins; C502010:claudin 16; D012964:Sodium; D003404:Creatinine; D008274:Magnesium; D002118:Calcium
Am J Physiol Renal Physiol. 2005 Oct;289(4):F793-802
15914779
J Exp Biol. 1997 Jan;200(Pt 2):295-302
9050237
J Clin Invest. 2003 Dec;112(12):1906-14
14679186
Nephron Physiol. 2006;103(1):p1-6
16352913
J Hypertens. 2004 Apr;22(4):803-10
15126923
J Am Soc Nephrol. 2007 Jun;18(6):1679-87
17475815
J Am Soc Nephrol. 2002 Apr;13(4):875-886
11912246
Pflugers Arch. 2001 Nov;443(2):297-305
11713657
Am J Hum Genet. 2006 Nov;79(5):949-57
17033971
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9424-9
9689096
Kidney Int Suppl. 2004 Oct;(91):S28-33
15461699
J Am Soc Nephrol. 2006 Mar;17(3):617-26
16421227
Science. 1999 Jul 2;285(5424):103-6
10390358
Comp Med. 2004 Apr;54(2):176-8
15134363
Pflugers Arch. 1981 Apr;390(1):30-7
7195550
Am J Physiol Renal Physiol. 2007 Jul;293(1):F166-77
17389678
Physiol Rev. 1985 Jul;65(3):760-97
2409564
J Clin Invest. 1997 Mar 15;99(6):1399-405
9077550
Pflugers Arch. 1981 Jan;389(2):175-6
7193859
J Clin Invest. 1973 Oct;52(10):2418-27
4729040
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2636-41
14983061
Trends Neurosci. 2001 Apr;24(4):207-11
11250003
Acta Physiol (Oxf). 2007 Apr;189(4):359-68
17367404
Kidney Int. 1982 Mar;21(3):445-58
6211566
J Clin Invest. 2008 Feb;118(2):619-28
18188451
Pflugers Arch. 1997 Aug;434(4):451-6
9211812
J Hypertens. 2004 Apr;22(4):683-5
15126906
Curr Protoc Mol Biol. 2006 Feb;Chapter 29:Unit 29A.2
18265382
J Biol Chem. 2007 Jun 8;282(23):17114-22
17442678
J Clin Chem Clin Biochem. 1987 Jun;25(6):357-61
3625134
Am J Physiol. 1989 Apr;256(4 Pt 2):R880-5
2539758