Claudin-2 and Claudin-12 Inform our Understanding of Intestinal Mineral Absorption

  • Author / Creator
    Saurette, Matthew
  • Hyperphosphatemia, elevated serum phosphate (Pi), is an electrolyte imbalance frequently associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD). There are many negative consequences of hyperphosphatemia including worsening renal function, secondary hyperparathyroidism, cardiovascular disease and mortality in this population and the general population. Therefore, reducing serum Pi is a clinical priority. Currently, the main strategies to lower serum Pi include dietary Pi restriction and phosphate-binding agents. However, restricting dietary Pi can be difficult as Western diets contain high amounts of Pi salts as additives and preservatives, which have greater bioavailability compared with organic sources. However, the mechanism responsible for altered bioavailability between the forms of Pi is unknown. Claudin-12 KO mice are a transgenic model with enhanced intestinal paracellular Pi permeability. When fed an inorganic Pi diet, they had increased Pi bioavailability compared to wild-type mice suggesting inorganic Pi moves preferentially via the paracellular pathway. Conversely, inhibiting Npt2b, the major transcellular intestinal Pi transporter with NTX-1942 reduced Pi bioavailability in wildtype mice on an organic phosphorus, but not an inorganic Pi diet. This suggests that Pi liberated from organic sources is absorbed transcellularly in the intestine, while inorganic Pi moves paracellularly leading to a higher bioavailability. Additionally, feeding claudin-12 KO mice an inorganic Pi diet results in hyperphosphatemia and is therefore a useful model for interrogating the causal link between high blood Pi, cardiovascular disease and mortality in the absence of renal dysfunction.

    Claudin-2 is a cation permeable claudin, expressed in the intestine and kidney like claudin-12. Previous cell culture work has inferred a role for claudin-2 in intestinal and renal calcium (re)absorption. To assess the role of claudin-2 in calcium homeostasis in vivo, metabolic balance studies were performed on wild-type and claudin-2 knockout mice. This revealed hypercalciuria and increased intestinal calcium absorption. Bi-ionic diffusion potential studies in Ussing chambers revealed reduced colonic calcium permeability without alterations in other segments. Analysis of wild-type and claudin-2 KO tibia’s revealed unaltered bone mineralization. Similarly, plasma calcium was not different between genotypes nor was intestinal or renal calciotropic gene expression. We therefore conclude that claudin-2 knockout mice have increased renal calcium excretion compensated by enhanced net calcium absorption secondary to reduced colonic secretion.

  • Subjects / Keywords
  • Graduation date
    Spring 2021
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.