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2015 ; 65
(5
): 1118-25
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MiR-217 mediates the protective effects of the dopamine D2 receptor on fibrosis
in human renal proximal tubule cells
#MMPMID25801876
Han F
; Konkalmatt P
; Chen J
; Gildea J
; Felder RA
; Jose PA
; Armando I
Hypertension
2015[May]; 65
(5
): 1118-25
PMID25801876
show ga
Lack or downregulation of the dopamine D2 receptor (D2R) increases the
vulnerability to renal inflammation independent of blood pressure in mice. Common
single nucleotide polymorphisms (SNPs) rs6276, 6277, and 1800497 in the human D2R
gene are associated with decreased receptor expression/function and hypertension.
Human renal proximal tubule cells from subjects carrying these SNPs have
decreased D2R expression and increased expression of profibrotic factors and
production of extracellular matrix proteins. We tested the hypothesis that the
D2R mediates these effects by regulating micro-RNA expression. In cells carrying
D2R SNPs, micro-RNAs (miRs)-217, miR-224, miR-335, and miR-1265 were
downregulated, whereas miR-1290 was upregulated >4-fold compared with those
carrying D2R wild-type alleles. However, only miR-217 was directly regulated by
D2R expression. In cells carrying D2R wild-type, miR-217 inhibitor increased the
expression of transforming growth factor (TGF)-?1, matrix metalloproteinase 3,
fibronectin 1, and collagen 1a, whereas miR-217 mimic had the opposite effect. In
cells carrying D2R SNPs, miR-217 mimic also decreased the expression of TGF?1 and
its targets. Wnt5a, a miR-217 target, was increased in cells carrying D2R SNPs
and decreased by miR-217 mimic but increased by miR-217 inhibitor in both cell
types. In cells carrying D2R wild-type, Wnt5a treatment increased TGF?1 while
silencing Ror2, a Wnt5a receptor, decreased TGF?1 and blunted the Wnt5a-induced
increase in cells carrying D2R wild-type. Our results show that renal proximal
tubule cells from subjects carrying D2R SNPs resulting in D2R downregulation have
increased TGF?1 that is mediated by decreased regulation of the
miR-217-Wnt5a-Ror2 pathway.