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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitriol / blood
  • Diet*
  • Disease Models, Animal
  • Femur / metabolism
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Gene Deletion
  • Genetic Predisposition to Disease
  • Glucuronidase / deficiency*
  • Glucuronidase / urine
  • Homeostasis
  • Hyperphosphatemia / blood
  • Hyperphosphatemia / enzymology*
  • Hyperphosphatemia / genetics
  • Hyperphosphatemia / urine
  • Hypophosphatemia, Familial / blood
  • Hypophosphatemia, Familial / enzymology*
  • Hypophosphatemia, Familial / genetics
  • Hypophosphatemia, Familial / urine
  • Intestinal Absorption
  • Kidney / enzymology*
  • Klotho Proteins
  • Mice, Knockout
  • Parathyroid Hormone / blood
  • Phenotype
  • Phosphates / blood
  • Phosphates / metabolism*
  • Phosphates / urine
  • Ubiquitin Thiolesterase / deficiency*
  • Ubiquitin Thiolesterase / genetics

Substances

  • Parathyroid Hormone
  • Phosphates
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • Glucuronidase
  • Klotho Proteins
  • Ubiquitin Thiolesterase
  • Uchl1 protein, mouse
  • Calcitriol