Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy.
OBJECTIVE
Solute carrier family 12 member 3 (SLC12A3) encodes a sodium/chloride transporter in kidneys. Previous reports suggest that Arg913Gln polymorphism in this gene is associated with diabetic nephropathy (DN), but the data appear to be inconsistent. Up to now, there is no biological evidence concerning the effects of SLC12A3 in DN. In this study, we aim to evaluate the genetic effects of the SLC12A3 gene and its Arg913Gln polymorphism with genetic and functional analyses.


METHODS
We genotyped SLC12A3 genetic polymorphisms including Arg913Gln in 784 non-diabetes controls and 633 type 2 diabetes (T2D) subjects with or without DN in a Malaysian population and performed a meta-analysis of the present and previous studies. We further analyzed the role of slc12a3 in kidney development and progress of DN in zebrafish and db/db mice.


RESULTS
We found that SLC12A3 Arg913Gln polymorphism was associated with T2D (p = 0.028, OR = 0.772, 95% CI = 0.612-0.973) and DN (p = 0.038, OR = 0.547, 95% CI = 0.308-0.973) in the Malaysian cohort. The meta-analysis confirmed the protective effects of SLC12A3 913Gln allele in DN (Z-value = -1.992, p = 0.046, OR = 0.792). Furthermore, with knockdown of zebrafish ortholog, slc12a3 led to structural abnormality of kidney pronephric distal duct at 1-cell stage. Slc12a3 mRNA and protein expression levels were upregulated in kidneys of db/db mice from 6, 12, and 26 weeks at the age.


CONCLUSIONS
The present study provided the first biological and further genetic evidence that SLC12A3 has genetic susceptibility in the development of DN, while the minor 913Gln allele in this gene confers a protective effect in the disease.
Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Norhashimah
N
Abu Seman
Bing
B
He
Juha R M
JR
Ojala
Wan Nazaimoon
WN
Wan Mohamud
Claes-Göran
CG
Östenson
Kerstin
K
Brismar
Harvest F
HF
Gu
D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
C578874:SLC12A3 protein, human; C578875:Slc12a3 protein, mouse; D064486:Solute Carrier Family 12, Member 3; D029961:Zebrafish Proteins