Genetic and functional effects of membrane metalloendopeptidase on diabetic nephropathy development.
OBJECTIVE
Vasopeptidase as an agent inhibits membrane metalloendopeptidase (MME, also known as neutral endopeptidase). MME is widely distributed in the body and particularly abundant in the kidney. The MME gene is located on chromosome 3q25.1 within a linkage region for diabetic nephropathy (DN). The present study aims to evaluate the genetic and functional effects of MME in the development of DN.


METHODS
A case-control genetic study of the MME gene in type 1 diabetes (T1D) patients with and without DN (n = 578/599) was performed. All subjects were selected from the Genetics of Kidneys in Diabetes study. Genotyping was performed with TagMan allelic discrimination. Mme mRNA and protein expression levels in kidney tissues of db/db mice at the ages of 5, 12 and 26 weeks were analyzed with TaqMan real-time RT-PCR and Western blot.


RESULTS
The haplotype A-C constructed with single nucleotide polymorphisms (SNPs) rs3796268A/G and rs3773885C/T in the MME gene was found to be associated with DN (p = 0.015, OR = 1.33, 95% CI 1.05-1.68) in female T1D patients. Further analyses of renal traits in T1D patients with DN and end-stage renal disease according to the genotypes of SNP rs3773885 indicated that the C allele carriers had higher serum creatinine levels compared to the subjects carrying T allele in both females and males. Mme expression at mRNA and protein levels was upregulated in kidneys of db/db mice at the ages of 12 and 26 weeks (p = 0.017 and <0.001) but not at the age of 5 weeks compared to the controls.


CONCLUSIONS
The present study provides the first evidence that MME has genetic and biological effects on the development of DN, and suggests that the inhibition of MME expression in the kidney with the agent of vasopeptidase may be a useful therapeutic approach for this disease.
Rolf Luft Center for Diabetes Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Dongying
D
Zhang
Tianwei
T
Gu
Elisabete
E
Forsberg
Suad
S
Efendic
Kerstin
K
Brismar
Harvest F
HF
Gu
D000328:Adult; D016022:Case-Control Studies; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000502:physiology*; D008875:Middle Aged
D008666:Metalloendopeptidases