MicroRNA-874-3p/ADAM (A Disintegrin and Metalloprotease) 19 Mediates Macrophage Activation and Renal Fibrosis After Acute Kidney Injury

Abstract

Inflammation and maladaptive repair play a crucial role in the development of chronic kidney disease and hypertension after acute kidney injury. To study the mechanisms involved in acute kidney injury-to-chronic kidney disease transition, we established a chronic renal fibrosis mouse model that was triggered by an initial ischemia/reperfusion–induced acute kidney injury (acute-chronic model). Downregulation of microRNA-874-3p during renal fibrosis was identified by a genome-wide RNA-sequencing and was further confirmed in cell-based assays, mouse models, and human samples. Overexpression of microRNA-874-3p in the kidneys markedly alleviated renal fibrosis, accompanied with decreased infiltrated macrophages and expression of α-smooth muscle actin, type I collagen, fibronectin, CCL (C-C motif chemokine ligand) 2, and ADAM (A Disintegrin and Metalloprotease) 19. ADAM19 is a target gene of microRNA-874-3p as shown by luciferase reporter assays and was upregulated in the acute-chronic model. Overexpression of ADAM19 directly induced the expression of fibrotic genes, CCL2, and macrophage infiltration in vivo. Depletion of macrophages using clodronate liposomes ameliorated the fibrogenic effects of ADAM19. Overexpression of ADAM19 also induced accumulation of the Notch1 intracellular domain, an upstream regulator of CCL2 expression, whereas Notch1 pathway antagonist N-(N-[3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester reduced CCL2 level in ADAM19-overexpressed cells. Collectively, microRNA-874-3p/ADAM19 mediates renal fibrosis after acute kidney injury by increasing macrophage infiltration via the Notch1/CCL2 pathway.