Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting

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Item Type:	Article
Title:	Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting
Creators Name:	Will, C., Breiderhoff, T., Thumfart, J., Stuiver, M., Kopplin, K., Sommer, K., Guenzel, D., Querfeld, U., Meij, I.C., Shan, Q., Bleich, M., Willnow, T.E. and Mueller, D.
Abstract:	Claudin16 (CLDN16) is critical for renal paracellular epithelial transport of Ca(2+) and Mg(2+) in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca(2+) and Mg(2+) homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction (FHHNC, OMIM 248250), we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca(2+) compensatory mechanisms like PTH and 1,25(OH)2D3 were significantly elevated. Also, gene expression profiling revealed transcriptional up-regulation of several Ca(2+) and Mg(2+) transport systems including Trpv5, Trpm6, and Calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg(2+) transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared to wildtype mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca(2+) and Mg(2+) homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca(2+) and Mg(2+) handling. Key words: Tight Junction, Knock out, Calcium, Claudin.
Keywords:	Claudin16, Magnesium, Calcium, Kidney, Tight Junction, Transgenic Animals, Animals, Mice
Source:	American Journal of Physiology Renal Physiology
ISSN:	0363-6127
Publisher:	American Physiological Society
Volume:	298
Number:	5
Page Range:	F1152-F1161
Date:	May 2010
Official Publication:	https://doi.org/10.1152/ajprenal.00499.2009
PubMed:	View item in PubMed

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