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2016 ; 27
(11
): 3447-3458
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Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates
with Calcium Nephrolithiasis in Patients
#MMPMID27036738
Nie M
; Bal MS
; Yang Z
; Liu J
; Rivera C
; Wenzel A
; Beck BB
; Sakhaee K
; Marciano DK
; Wolf MT
J Am Soc Nephrol
2016[Nov]; 27
(11
): 3447-3458
PMID27036738
show ga
Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported
that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal
calcium channel TRPV5. This channel is crucial for calcium reabsorption in the
distal convoluted tubule (DCT). Recently, mutations in the gene encoding Mucin-1
(MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease,
the same disease caused by UMOD mutations. Because of the similarities between
UMOD and MUC1 regarding associated disease phenotype, protein structure, and
function as a cellular barrier, we examined whether urinary MUC1 also enhances
TRPV5 channel activity and protects against nephrolithiasis. We established a
semiquantitative assay for detecting MUC1 in human urine and found that, compared
with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had
significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in
the thick ascending limb, DCT, and collecting duct. Applying whole-cell
patch-clamp recording of HEK cells, we found that wild-type but not disease
mutant MUC1 increased TRPV5 activity by impairing dynamin-2- and
caveolin-1-mediated endocytosis of TRPV5. Coimmunoprecipitation confirmed a
physical interaction between TRPV5 and MUC1. However, MUC1 did not increase the
activity of N-glycan-deficient TRPV5. MUC1 is characterized by variable number
tandem repeats (VNTRs) that bind the lectin galectin-3; galectin-3 siRNA but not
galectin-1 siRNA prevented MUC1-induced upregulation of TRPV5 activity.
Additionally, MUC1 lacking VNTRs did not increase TRPV5 activity. Our results
suggest that MUC1 forms a lattice with the N-glycan of TRPV5 via galectin-3,
which impairs TRPV5 endocytosis and increases urinary calcium reabsorption.
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