Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model

Author:

Tserga Aggeliki1ORCID,Saulnier-Blache Jean Sébastien23,Palamaris Kostantinos4ORCID,Pouloudi Despoina4,Gakiopoulou Harikleia4,Zoidakis Jerome15ORCID,Schanstra Joost Peter23,Vlahou Antonia1ORCID,Makridakis Manousos1ORCID

Affiliation:

1. Biomedical Research Foundation, Academy of Athens, Department of Biotechnology, Soranou Efessiou 4, 11527 Athens, Greece

2. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1297, Institute of Cardiovascular and Metabolic Disease, 31432 Toulouse, France

3. Department of Biology, Université Toulouse III Paul-Sabatier, 31062 Toulouse, France

4. 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 34400 Athens, Greece

5. Department of Biology, National and Kapodistrian University of Athens, 15701 Zografou, Greece

Abstract

Diabetic kidney disease (DKD) is characterized by histological changes including fibrosis and inflammation. Evidence supports that DKD is mediated by the innate immune system and more specifically by the complement system. Using Ins2Akita T1D diabetic mice, we studied the connection between the complement cascade, inflammation, and fibrosis in early DKD. Data were extracted from a previously published quantitative-mass-spectrometry-based proteomics analysis of kidney glomeruli of 2 (early DKD) and 4 months (moderately advanced DKD)-old Ins2Akita mice and their controls A Spearman rho correlation analysis of complement- versus inflammation- and fibrosis-related protein expression was performed. A cross-omics validation of the correlation analyses’ results was performed using public-domain transcriptomics datasets (Nephroseq). Tissue sections from 43 patients with DKD were analyzed using immunofluorescence. Among the differentially expressed proteins, the complement cascade proteins C3, C4B, and IGHM were significantly increased in both early and later stages of DKD. Inflammation-related proteins were mainly upregulated in early DKD, and fibrotic proteins were induced in moderately advanced stages of DKD. The abundance of complement proteins with fibrosis- and inflammation-related proteins was mostly positively correlated in early stages of DKD. This was confirmed in seven additional human and mouse transcriptomics DKD datasets. Moreover, C3 and IGHM mRNA levels were found to be negatively correlated with the estimated glomerular filtration rate (range for C3 rs = −0.58 to −0.842 and range for IGHM rs = −0.6 to −0.74) in these datasets. Immunohistology of human kidney biopsies revealed that C3, C1q, and IGM proteins were induced in patients with DKD and were correlated with fibrosis and inflammation. Our study shows for the first time the potential activation of the complement cascade associated with inflammation-mediated kidney fibrosis in the Ins2Akita T1D mouse model. Our findings could provide new perspectives for the treatment of early DKD as well as support the use of Ins2Akita T1D in pre-clinical studies.

Funder

Hellenic Foundation for Research and Innovation

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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