Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *.

[aromatase deficiency]

Kidney stones increase after menopause , suggesting a role for estrogen deficiency . ArKO mice have hypercalciuria and lower levels of calcium transport proteins , whereas levels of the klotho protein are elevated . Thus , estrogen deficiency is sufficient to cause altered renal calcium handling .The incidence of renal stones increases in women after menopause , implicating a possible role for estrogen deficiency . We used the aromatase deficient (ArKO ) mouse , a model of estrogen deficiency , to test the hypothesis that estrogen deficiency would increase urinary calcium excretion and alter the expression of molecular regulators of renal calcium reabsorption .Adult female wildtype (WT ), ArKO , and estradiol-treated ArKO mice (n = 5 -12 /group ) were used to measure urinary calcium in the fed and fasting states , relative expression level of some genes involved in calcium reabsorption in the distal convoluted tubule by real-time PCR , and protein expression by Western blotting or immunohistochemistry . Plasma membrane calcium ATPase (PMCA ) activity was measured in kidney membrane preparations . ANOVA was used to test for differences between groups followed by posthoc analysis with Dunnett 's test .Compared with WT , urinary Ca :Cr ratios were elevated in ArKO mice , renal mRNA levels of transient receptor potential cation channel vallinoid subfamily member 5 (TRPV 5 ), TRPV 6 , calbindin-D 28 k , the Na +/Ca + exchanger (NCX 1 ), and the PMCA 1 b were significantly decreased , and klotho mRNA and protein levels were elevated . Estradiol treatment of ArKO mice normalized urinary calcium excretion , renal mRNA levels of TRPV 5 , calbindin-D (28 k ), PMCA 1 b , and klotho , as well as protein levels of calbindin-D 28 k and Klotho . ArKO mice treated with estradiol had significantly greater PMCA activity than either untreated ArKO mice or WT mice .Estrogen deficiency caused by aromatase inactivation is sufficient for renal calcium loss . Changes in estradiol levels are associated with coordinated changes in expression of many proteins involved in distal tubule calcium reabsorption . Estradiol seems to act at the genomic level by increasing or decreasing (klotho ) protein expression and nongenomically by increasing PMCA activity . PMCA , not NCX 1 , is likely responsible for extruding calcium in response to in vivo estradiol hormonal challenge . These data provide potential mechanisms for regulation of renal calcium handling in response to changes in serum estrogen levels .

Diseases
Validation

Diseases presenting "renal stones" symptom

aromatase deficiency

cystinuria

neonatal adrenoleukodystrophy

primary hyperoxaluria type 1

This symptom has already been validated