Format

Send to

Choose Destination
Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F353-F363. doi: 10.1152/ajprenal.00411.2017. Epub 2018 Apr 18.

Ubiquitin COOH-terminal hydrolase L1 deletion is associated with urinary α-klotho deficiency and perturbed phosphate homeostasis.

Author information

1
Kidney Research Centre, The Ottawa Hospital , Ottawa, Ontario , Canada.
2
Ottawa Hospital Research Institute, The Ottawa Hospital , Ottawa, Ontario , Canada.
3
Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa , Ottawa, Ontario , Canada.
4
Department of Physiology, University of Alberta , Edmonton, Alberta , Canada.
5
Membrane Protein Disease Research Group, University of Alberta , Edmonton, Alberta , Canada.
6
Department of Pediatrics, University of Alberta , Edmonton, Alberta , Canada.
7
Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, Ontario , Canada.

Abstract

Loss of ubiquitin COOH-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme required for neuronal function, led to hyperphosphatemia accompanied by phosphaturia in mice, while calcium homeostasis remained intact. We therefore investigated the mechanisms underlying the phosphate imbalance in Uchl1-/- mice. Interestingly, phosphaturia was not a result of lower renal brush border membrane sodium-phosphate cotransporter expression as sodium-phosphate cotransporter 2a and 2c expression levels was similar to wild-type levels. Plasma parathyroid hormone and fibroblast growth factor 23 levels were not different; however, fibroblast growth factor 23 mRNA levels were significantly increased in femur homogenates from Uchl1-/- mice. Full-length and soluble α-klotho levels were comparable in kidneys from wild-type and Uchl1-/- mice; however, soluble α-klotho was reduced in Uchl1-/- mice urine. Consistent with unchanged components of 1,25(OH)2D3 metabolism (i.e., CYP27B1 and CYP24A1), sodium-phosphate cotransporter 2b protein levels were not different in ileum brush borders from Uchl1-/- mice, suggesting that the intestine is not the source of hyperphosphatemia. Nonetheless, when Uchl1-/- mice were fed a low-phosphate diet, plasma phosphate, urinary phosphate, and fractional excretion of phosphate were significantly attenuated and comparable to levels of low-phosphate diet-fed wild-type mice. Our findings demonstrate that Uchl1-deleted mice exhibit perturbed phosphate homeostasis, likely consequent to decreased urinary soluble α-klotho, which can be rescued with a low-phosphate diet. Uchl1-/- mice may provide a useful mouse model to study mild perturbations in phosphate homeostasis.

KEYWORDS:

UCH-L1; UCHL1; hyperphosphatemia; phosphate; α-klotho

PMID:
29667913
DOI:
10.1152/ajprenal.00411.2017
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center