Tubular Transport Mechanism
Renal Adaptation
Mechanism to Calcium Load and Novel Molecular Pathway of Magnesium Transport
The kidney plays an
important role in maintaining homeostasis of calcium and magnesium. Tubular
reabsorption of the filtered ion determines the final urinary concentration.
Distal convoluted tubule (DCT) is the fine tune of calcium transport and
hormones and drugs modulate calcium reabsorption in this segment. The recent
discovered transient receptor potential (TRP) family, including TRPV5 and TRPM6
are considered as the gate keeper of calcium and magnesium transport in DCT.
Factors regulating TRPV5 are well-defined, but less is recognized for TRPM6.
Renal epithelial calcium transport in DCT need cooperative machinery and
calbindin-D (CBD) 28k is the essential molecule responsible for cytosolic
calcium transport. Our previous study has demonstrated an increase in urinary
calcium excretion in CBD28k knockout mice, indicating a defect in DCT calcium
transport. With the capacity to reabsorb calcium, DCT may act as compensatory
adaptor to reduce urinary calcium excretion in response to calcium load. In the
neonates, this adaptation mechanism may not develop well to prevent renal
calcium wasting. In the present study we aim to investigate the role of calcium
reabsorption in DCT in reducing urinary calcium excretion. Our previous studies
have shown that administration with gentamicin induces significant calciuria. We
will compare the drug effect on calciuria in wild type and CBD28k knockout mice
in response to administration of gentamicin and furosemide respectively. The
role of newly identified regulators of TRPM6 in drug-induced urinary magnesium
wasting is not clear. Immunosuppressants and gentamicin will be injected to
induce magnesiuria and their effects on TRPM6 and hepatocyte nuclear factor 1B,
epidermal growth factor and cyclin M2 will be examined. The probable involved
signaling pathway will be analyzed in a cell model.
