Long Noncoding RNA Arid2-IR Is a Novel Therapeutic Target for Renal Inflammation

Abstract

Increasing evidence shows that microRNAs play an important role in kidney disease. However, functions of long noncoding RNAs (lncRNAs) in kidney diseases remain undefined. We have previously shown that TGF-β1 plays a diverse role in renal inflammation and fibrosis and Smad3 is a key mediator in this process. In this study, we used RNA-sequencing to identify lncRNAs related to renal inflammation and fibrosis in obstructive nephropathy induced in Smad3 wild-type and knockout mice. We found that Arid2-IR was a Smad3-associated lncRNA as a Smad3 binding site was found in the promoter region of Arid2-IR and deletion of Smad3 abolished upregulation of Arid2-IR in the diseased kidney. In vitro knockdown of Arid2-IR from tubular epithelial cells produced no effect on TGF-β-induced Smad3 signaling and fibrosis but inhibited interleukin-1β-stimulated NF-κB-dependent inflammatory response. In contrast, overexpression of Arid2-IR promoted interleukin-1β-induced NF-κB signaling and inflammatory cytokine expression without alteration of TGF-β1-induced fibrotic response. Furthermore, treatment of obstructed kidney with Arid2-IR shRNA blunted NF-κB-driven renal inflammation without effect on TGF-β/Smad3-mediated renal fibrosis. Thus, Arid2-IR is a novel lncRNA that functions to promote NF-κB-dependent renal inflammation. Blockade of Arid2-IR may represent a novel and specific therapy for renal inflammatory disease.

Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development

“…Smad3 −/− and Smad3 +/+ bone marrow cells were harvested and transfected with (100 nM) nonsense control (siN05815122147, RIBOBIO) and siRNA against E4BP4 (5′-GAUGAGGGUGUAGUGGGCAAGUCUU-3′) on Days 0 and 4 as described previously53. The bone marrow cells were ex vivo differentiated into NK cells according to the protocol of Fathman et al 54…”

Investigating long noncoding RNAs using animal models

“…shRNA-mediated downregulation of Miat (also known as Gomafu) in the medial prefrontal cortex of the brain promotes anxiety-like behaviors (75), while local siRNA-mediated downregulation of Munc, which is specifically expressed in skeletal muscle, impairs myogenesis (76). Additionally, the use of an shRNA to revert the upregulation of Arid2-IR in the mouse kidney following renal inflammation also reverts the biochemical signatures of this condition (77). Future work using mutant-and virus-mediated strategies will likely reveal additional phenotypes directly attributable to lncRNAs.…”

Long non-coding RNAs–towards precision medicine in diabetic kidney disease?

“…Since TGFβ signals via Smad3, this approach identified LNCRNAs involved in the Smad3 signalling pathway. It was found that ARID2-IR LNCRNA functions to block nuclear factor-κB (NF-κB) dependent renal inflammation [11]. There are currently no studies which have measured ARID2-IR in animal models of DKD.…”