SFEBES2009 Poster Presentations Diabetes and metabolism (59 abstracts)
Nuf mice with an activating calcium sensing receptor mutation, Leu723Gln, have a metabolic acidosis and impaired urinary acidification
Fadil Hannan 1 , M Andrew Nesbit 1 , Chris Esapa 2 , Simona Di Pretoro 2 , Mary Lyon 2 , Roger Cox 2 & Rajesh Thakker 1
1Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Medical Research Council, Harwell, Oxfordshire, UK.
The calcium sensing receptor (CaSR) is a G protein coupled receptor that is expressed in type A intercalated cells of the distal convoluted tubule and cortical collecting ducts, where it is involved in renal proton excretion. We have therefore investigated the Nuf mouse, which has an activating CaSR mutation (Leu723Gln) that leads to hypocalcaemia, hypercalciuria, renal calcification, a urinary concentrating defect, and cataracts, for disturbances in acid-base homeostasis. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions and housed in metabolic cages with ad libitum feeding for 4 days to allow for acclimatisation. The day 4 urine samples were obtained for measurement of pH, and venous whole blood samples were collected and analysed immediately using an i-stat blood gas analyser (Abbott diagnostics). Homozygous affected (Nuf/Nuf) mice (n=17) had a significantly more alkaline urine when compared to wild-type litter mates (n=21) (pH=7.1±0.07 vs 6.6±0.04, P<0.0001). In addition, Nuf/Nuf mice (n=15) when compared to wild-type litter mates (n=15), had a significantly reduced venous whole blood pH (pH=7.29±0.016 vs 7.34±0.01, P=0.01) that was associated with significantly lower venous whole blood bicarbonate and base excess levels (blood bicarbonate=17.3±0.52 vs 21.1±0.53 mmol/l, P<0.0001; base excess=−9.29±0.69 vs −4.53±0.61, P<0.0001), These results demonstrate that Nuf/Nuf mice have a metabolic acidosis that is related to a defect of urinary acidification, and indicates that the CaSR plays a role in the regulation of systemic acid-base homeostasis. In addition, the presence of alkaline urine may explain why patients with activating CaSR mutations are susceptible to renal calcification and stone formation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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