Novel molecular pathways in renal Mg2+ transport: a guided tour along the nephron.

PURPOSE OF REVIEW: This review highlights recent advances in renal magnesium (Mg) handling. The understanding of the molecular processes of epithelial Mg transport has expanded considerably due to the identification of novel genes involved in hypomagnesemic disorders. RECENT FINDINGS: Mg deficiency remains one of the most common electrolyte disorders. Detailed genetic analysis of families with inherited forms of hypomagnesemia has led to the identification of new genes involved in Mg homeostasis. As such, familial hypomagnesemia has been linked to mutations in the claudin-16/19 complex located in the thick ascending limb. Moreover, the pro-epidermal growth factor, the potassium channels Kv1.1 and Kir4.1, and the hepatocyte nuclear factor 1B have recently been identified as causative factors in syndromes of hereditary hypomagnesemia. These proteins play key roles in regulating electrolyte balance within the distal convoluted tubule, either by directly affecting the epithelial Mg channel, transient receptor potential channel melastatin member 6, or by altering the driving force for Mg influx via the channel. SUMMARY: Recent genetic and molecular studies have further elucidated the processes that govern renal Mg transport and hence systemic Mg balance. This has provided us with new tools to understand the molecular pathology behind hypomagnesemia.

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

UNLABELLED: 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. INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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 (TRPV5), TRPV6, calbindin-D28k, the Na+/Ca+ exchanger (NCX1), and the PMCA1b were significantly decreased, and klotho mRNA and protein levels were elevated. Estradiol treatment of ArKO mice normalized urinary calcium excretion, renal mRNA levels of TRPV5, calbindin-D(28k), PMCA1b, and klotho, as well as protein levels of calbindin-D28k and Klotho. ArKO mice treated with estradiol had significantly greater PMCA activity than either untreated ArKO mice or WT mice. CONCLUSIONS: 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 NCX1, 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.