Gut bacteria and lipocalin 2 interplay mediates inflammation and arteriosclerosis in type‐II diabetic kidney

Abstract

Genome‐wide association studies report significant correlations of unique gut microbiota and their metabolites with type II diabetes (T2D). Further, a growing body of evidence suggest the gut microbiota plays an important role in the onset and progression of Diabetic nephropathy. Lipocalin 2 (Lcn2) is a small secretory glycoprotein that can act as a mediator or modulator of inflammatory processes in various pathologies. Recently, in addition to its role as a potential biomarker of diseases, Lcn2 was shown to contribute towards the progression of nephrectomy‐induced chronic kidney disease (CKD). High levels of Lcn2 have been reported in obesity and type II diabetes (T2D) however, its role in T2D nephropathy remains unknown. Therefore, the purpose of this study was to investigate the relationship of gut microbiota and Lcn2 in T2D and whether Lcn2 contributes to the development of renal arteriosclerosis and dysfunction. Three‐month‐old mice homozygous for Leprdb mutation (db/db) were used as type – II diabetes models and mice heterozygous for Leprdb mutation (db/+, non‐diabetic) served as controls. Lcn2 was upregulated in db/db kidney compared to db/+. There was differential expression of Lcn2 in the fecal and plasma samples of db/db mice compared to db/+ and correlated with gut and renal inflammation. In db/db mice, high Lcn2 protein levels correlated with poor renal function. Microbial DNA isolation from stools and 16S rRNA sequencing showed abundance of bacteria at phyla level in db/db mice compared to db/+ and rich in alpha and beta diversity. The db/db samples showed decreased Firmicutes/Bacteriodetes ratio and increased Proteobacteria compared to db/+. Further, Actinobateria was absent in the db/db samples. The db/db kidneys showed increased vascular adhesion molecules and inflammation, reduction of vascularity and decreased blood flow. Barium angiography revealed narrowing of renal, segmental and interlobar arteries and rarefaction of terminal branches in db/db kidneys compared to db/+. The db/db kidneys showed injury, vascular thickening and reduced elastin. Our findings of altered gut microbiome and upregulation of Lcn2 suggests a significant crosstalk between the gut and kidney and is associated with renal inflammation, arteriosclerosis and dysfunction.Support or Funding InformationNIH: DK116591 and DK104653 to Utpal SenAHA: 15SDG25840013 to Sathnur Pushpakumar