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Urinary Acidification Does Not Explain the Absence of Nephrocalcinosis in a Mouse Model of Familial Hypomagnesaemia
Amr Al-Shebel1, Geert Michel2, Tilman Breiderhoff1
1Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Augustenburger Platz 1, 13353 Berlin, Germany.
Insights
Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is linked to CLDN16 mutations. Urine acidification does not solely prevent nephrocalcinosis in claudin-16 deficient mice, as shown by experiments involving B1 subunit ablation.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Mutations in Claudin-16 (CLDN16) cause familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC), leading to kidney damage.
- Claudin-16 deficient mice exhibit hypomagnesemia and hypercalciuria but lack nephrocalcinosis, suggesting a protective mechanism.
- Urine acidification is hypothesized to inhibit calcium salt formation, potentially explaining the absence of nephrocalcinosis in these mice.
Purpose of the Study:
- To investigate the role of urine pH in preventing nephrocalcinosis in a mouse model lacking claudin-16.
- To determine if alkalinizing urine in claudin-16 deficient mice would induce nephrocalcinosis.
Main Methods:
- Generated a mouse model lacking both claudin-16 and the B1 subunit of vesicular ATPase.
- This genetic modification aimed to increase urinary pH by disrupting proton transport.
- Monitored for the development of nephrocalcinosis in the modified mice.
Main Results:
- Mice lacking both claudin-16 and the B1 subunit exhibited alkalinized urine.
- Despite the increased urinary pH, these mice did not develop nephrocalcinosis.
- This indicates that urine acidification is not the sole factor preventing kidney calcification in claudin-16 deficient mice.
Conclusions:
- The absence of nephrocalcinosis in claudin-16 deficient mice is not solely due to acidic urine.
- Other factors beyond urine pH likely play a crucial role in preventing kidney stone formation in this genetic condition.
- Further research is needed to elucidate the complete mechanism protecting against nephrocalcinosis in the absence of functional claudin-16.
Abstract:
Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice.
