Claudin 2 and Hypercalciuria—Of Mice And

RESEARCH HIGHLIGHTS Credit: Image courtesy of A. Yu and J. Curry, University of Kansas Medical Center, USA STONES Claudin 2 and hyper calciuria — of mice and men Claudin 2 is a regulator of calcium and glomerular calcium filtration with kidney stones and 187,639 excretion and could be a treatment were comparable between Cldn2–/y controls and identifying 9 SNPs that They began target for patients with urolithiasis, mice and wild-type littermates, were significantly associated with by studying according to new data published in suggesting that this difference is risk of nephrocalcinosis (P < 0.05). the Journal of Clinical Investigation. due to a decrease in renal calcium These data were further supported by claudin Hypercalciuria is integral to the reabsorption in Cldn2–/y mice as a genome analysis of an Iranian family, 2- knockout pathogenesis of stone formation, result of impaired proximal tubule who had previously been shown to (Cldn2–/y) which is likely to arise via calcium paracellular calcium transport. harbour a rare missense mutation mice deposition in the renal papilla. The Leading on from the observation in CLDN2 that led to obstructive … aetiology of hypercalciuria is somewhat of hypercalciuria, the team then azoospermia. Both male and female confirming uncertain but is thought to include investigated whether Cldn2–/y mice members of this family also had that they increased bone resorption, calcium were prone to nephrocalcinosis. marked hypercalciuria. are indeed hyperabsorption in the intestine and Accordingly, they observed abundant “Our premise — that defects in hypercalciuric reduced renal reabsorption. Calcium mineral deposits in the renal papillae proximal tubule calcium handling reabsorption occurs largely in the of 6- month- old and 1- year- old lead to papillary calcification and, proximal tubule, where ~60% of Cldn2–/y mice. Examination of therefore, kidney stone disease — calcium filtered by the glomerulus is 5- month- old mice using transmission represents a paradigm shift in reabsorbed, most likely via paracellular electron microscopy revealed that thinking about tubular calcium diffusion. This transport is mediated these deposits were present in mice handling,” corresponding author by claudins — a family of membrane before they became easily detected Alan Yu tells Nature Reviews Urology. proteins found at epithelial tight at 6 months and contained cells “We are not the first to postulate the junctions, which act as charge- selective originating from the ascending and importance of the proximal tubule: channels and regulate the movement descending limbs of the loops of Fred Coe, Elaine Worcester and of solutes across the epithelium. Henle, indicating that this location was Andrew Evan at Chicago and Indiana Claudin 2 is of particular also the origin of the mineral deposits. were the real pioneers and have interest as it is permeable to both This phenotype — hypercalciuria been trying to make a case for this sodium and calcium and is highly secondary to both proximal tubular in recent years, but I think our study expressed in the proximal tubule calcium wasting and increased really strengthens this argument.” and the descending loop of Henle. intestinal calcium absorption The data presented suggest a Furthermore, the proximal tubules with papillary mineral deposition possible new target for clinical of claudin 2-knockout mice exhibit in the thin limbs of the loops kidney stone therapies. “Perhaps increased fractional excretion of of Henle — is reminiscent of interventions to increase proximal calcium, suggesting that claudin 2 the phenotype of patients with tubule calcium reabsorption (and mediates paracellular calcium idiopathic hypercalciuria and kidney hence reduce calcium delivery to reabsorption in the proximal tubule. stone disease. Thus, the group the papilla) might be more effective Thus, Curry and colleagues hypothesized that CLDN2 variants at reducing stone incidence, than investigated whether claudin 2 loss might be involved in the pathogenesis simply reducing overall urine calcium predisposes mice to nephrocalcinosis of human kidney stone disease. concentration and calcium oxalate and leads to kidney stone formation Previous genome- wide studies did supersaturation,” comments Yu. in a similar manner to stone not include the X chromosome Annette Fenner formation in humans. They began in their analysis, so Curry and ORIGINAL ARTICLE Curry, J. N. et al. Claudin-2 by studying claudin 2-knockout colleagues studied the association deficiency associates with hypercalciuria in mice – and human kidney stone disease. J. Clin. Invest. 130, (Cldn2 /y) mice (Cldn2 is located between 12 single-nucleotide 1948–1960 (2020) on the X chromosome), confirming polymorphisms (SNPs) in the RELATED ARTICLE Sivaguru, M. et al. GeoBioMed that they are indeed hypercalciuric. CLDN2 locus and stone risk, sheds new light on human kidney stone crystalli- zation and dissolution. Nat. Rev. Urol. 17, 1–2 (2020) However, serum calcium levels analysing a total of 11,130 patients NATURE REVIEWS | UROLOGY VOLUME 17 | MAY 2020 | 255.

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