Abstract
Albumin absorbed by renal tubular epithelial cells induces inflammation
and plays a key role in promoting diabetic kidney disease (DKD)
progression. Macrophages are prominent inflammatory cells in the kidney,
and their role there is dependent on their phenotypes. However, whether
albuminuria influences macrophage phenotypes and underlying mechanisms
during the development of DKD is still unclear. We found that M1
macrophage-related markers were increased in diabetes mellitus (DM)
mouse renal tissues with the development of DKD, and coculture of
extracellular vesicles (EVs) from human serum albumin (HSA)-induced HK-2
cells with macrophages induced macrophage M1 polarization in the
presence of lipopolysaccharide (LPS). Through a bioinformatic analysis,
miR-199a-5p was selected and found to be increased in EVs from
HSA-induced HK-2 cells and in urinary EVs from DM patients with
macroalbuminuria. Tail-vein injection of DM mice with EVs from
HSA-induced HK-2 cells induced kidney macrophage M1 polarization and
accelerated the progression of DKD through miR-199a-5p. miR-199a-5p
exerted its effect by targeting Klotho, and Klotho induced macrophage M2
polarization through the Toll-like receptor 4 (TLR4) pathway both in vivo and in vitro.
In summary, miR-199a-5p from HSA-stimulated HK-2 cell-derived EVs
induces M1 polarization by targeting the Klotho/TLR4 pathway and further
accelerates the progression of DKD.