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Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Genetic and functional effects of membrane metalloendopeptidase on diabetic nephropathy development
Dongying Zhang1, Tianwei Gu, Elisabete Forsberg
1Rolf Luft Center for Diabetes Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Background/Aims:
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.
Insights
The membrane metalloendopeptidase (MME) gene is linked to diabetic nephropathy (DN). MME genetic variations and increased kidney expression in mice suggest MME plays a role in DN development and may be a therapeutic target.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Membrane metalloendopeptidase (MME) is a key enzyme in kidney function, and its gene is located in a region associated with diabetic nephropathy (DN).
- Understanding the role of MME in DN is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the genetic and functional impact of the MME gene in the development of diabetic nephropathy.
- To explore MME as a potential therapeutic target for DN.
Main Methods:
- A case-control genetic study involving type 1 diabetes (T1D) patients with and without DN.
- Analysis of MME gene polymorphisms using TagMan allelic discrimination.
- Quantification of Mme mRNA and protein expression in the kidneys of db/db mice at various ages.
Main Results:
- A specific MME haplotype (A-C) was associated with DN in female T1D patients.
- Carriers of the C allele at SNP rs3773885 showed higher serum creatinine levels.
- Mme expression was upregulated in the kidneys of db/db mice at 12 and 26 weeks of age.
Conclusions:
- This study provides the first evidence linking MME to the genetic and biological mechanisms underlying DN.
- Inhibiting MME in the kidney may represent a promising therapeutic strategy for managing DN.
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