title: Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy.
abstract: Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a(-/-) mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a(-/-) than in the kidneys of wild-type mice. Notably, miR-146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1β and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a(-/-) mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a(-/-) mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN.
authors.affiliation: Department of Diabetes Complications.
authors.forename: Kirti
authors.initials: K
authors.lastname: Bhatt
authors.affiliation: Department of Diabetes Complications.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Lanting
authors.affiliation: Department of Diabetes Complications.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Diabetes Complications.
authors.forename: Sailee
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Diabetes Complications.
authors.forename: Marpadga A
authors.initials: MA
authors.lastname: Reddy
authors.affiliation: Department of Molecular and Cellular Biology, and Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope National Medical Center, Duarte, California.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Magilnick
authors.affiliation: Department of Molecular and Cellular Biology, and.
authors.forename: Mark
authors.initials: M
authors.lastname: Boldin
authors.affiliation: Department of Diabetes Complications, RNatarajan@coh.org.
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology*; D007249:Inflammation / Q000209:etiology; D008264:Macrophages; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse
keywords: diabetic nephropathy; inflammation; macrophages; microRNA; renal fibrosis