Kidney-specific claudin-2 deficiency leads to medullary nephrocalcinosis in mice
Christine V. Behm, Duuamene Nyimanu, Ony Araujo Galdino, Sadhana Kanoo, Young Chul Kim, Natalia Lopez, Helen Goodluck, Peter S. Rowe, Andrew P. Evan, André J. Sommer, Matthew N. Barr, Tracy Punshon, Volker Vallon, Brian P. Jackson, James C. Williams Jr., Alan S.L. Yu
Christine V. Behm, Duuamene Nyimanu, Ony Araujo Galdino, Sadhana Kanoo, Young Chul Kim, Natalia Lopez, Helen Goodluck, Peter S. Rowe, Andrew P. Evan, André J. Sommer, Matthew N. Barr, Tracy Punshon, Volker Vallon, Brian P. Jackson, James C. Williams Jr., Alan S.L. Yu
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Research Article Metabolism Nephrology

Kidney-specific claudin-2 deficiency leads to medullary nephrocalcinosis in mice

Abstract

Deposits of hydroxyapatite called Randall’s plaques are found in the renal papilla of calcium oxalate kidney stone formers and likely serve as the nidus for stone formation, but their pathogenesis is unknown. Claudin-2 is a paracellular ion channel that mediates calcium reabsorption in the renal proximal tubule. To investigate the role of renal claudin-2, we generated kidney tubule–specific claudin-2 conditional KO mice (KS-Cldn2 KO). KS-Cldn2 KO mice exhibited transient hypercalciuria in early life. Normalization of urine calcium was accompanied by a compensatory increase in expression and function of renal tubule calcium transporters, including in the thick ascending limb. Despite normocalciuria, KS-Cldn2 KO mice developed papillary hydroxyapatite deposits, beginning at 6 months of age, that resembled Randall’s plaques and tubule plugs. Bulk chemical tissue analysis and laser ablation–inductively coupled plasma mass spectrometry revealed a gradient of intrarenal calcium concentration along the corticomedullary axis in normal mice that was accentuated in KS-Cldn2 KO mice. Our findings provide evidence for the “vas washdown” hypothesis for Randall’s plaque formation and identify the corticomedullary calcium gradient as a potential target for therapies to prevent kidney stone disease.

Authors

Christine V. Behm, Duuamene Nyimanu, Ony Araujo Galdino, Sadhana Kanoo, Young Chul Kim, Natalia Lopez, Helen Goodluck, Peter S. Rowe, Andrew P. Evan, André J. Sommer, Matthew N. Barr, Tracy Punshon, Volker Vallon, Brian P. Jackson, James C. Williams Jr., Alan S.L. Yu

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Figure 7

Nephrocalcinosis in older kidney-specific Cldn2-KO mice.

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Nephrocalcinosis in older kidney-specific Cldn2-KO mice. (A) Alizarin re...
(A) Alizarin red staining of the renal inner medulla of 1-year-old female Cre– and Cre+ mice. Scale bar: 400 µm. (B) Left: Papilla of a 16 month-old female Cre+ mouse stained with alizarin red. Right: High-magnification view of Yasue-stained section showing large intratubular plugs and smaller interstitial granular deposits (yellow arrows). (C) Infrared analysis of mineral deposits. Top panels: Yasue-stained section showing extensive mineral deposition in renal papilla. Inset: False-color representation of spectrum field with infrared microscope; square is 400 x 400 μm. Bottom panels: Spectra from mineral locations 1–3, indicated in the inset, along with standard spectra for apatite and calcite (calcium carbonate). (D) Micro-CT scans of the kidneys from A at bone density setting to detect mineral deposits. (E) Quantitation of mineral volume as a proportion of total kidney volume (P = 0.0036 for effect of genotype by 3-way ANOVA).