The long noncoding RNA Ptprd-IR is a novel molecular target for TGF-β1-mediated nephritis

Abstract

The role of microRNAs (miRNAs) in chronic kidney disease (CKD) is relatively well established, but much less is known about the role(s) of long noncoding RNAs (lncRNAs). Transforming growth factor β1 (TGF-β1) mediates inflammatory and fibrogenic signaling in CKD via the transcription factor Smad3; however, the extent of lncRNAs-based regulation of TGF-β1 signaling in CKD remains unknown. Herein, we identified np_4334, a lncRNA we named Ptprd-IR, whose promoter contains a highly-conserved site for Smad3 binding. Smad3 knockout (KO) eliminated Ptprd-IR upregulation in a murine model of obstructive nephropathy. Furthermore, Ptprd-IR KO in renal tubular epithelial cell cultures blocked TGF-β1- and interleukin-1β (IL-1β)-mediated NF-κB inflammatory signaling but did not impact TGF-β1-triggered Smad3 pathway activity and fibrosis. Accordingly, Ptprd-IR overexpression (OE) upregulated TGF-β1- and IL-1β-mediated NF-κB pathway activation and production of pro-inflammatory cytokines but did not influence TGF-β1-mediated fibrogenic signaling. Additionally, transfection of obstructed kidneys with Ptprd-IR-directed shRNA attenuated the inflammatory response via NF-κB but did not impact TGF-β1/Smad3-mediated fibrogenesis. Overall, our findings demonstrate that the lncRNA Ptprd-IR stimulates the inflammatory response in kidneys and advocate Ptprd-IR as a possible therapeutic target for CKD.

Keywords: CKD; Chronic kidney disease; Nephritis; TGF-β1; lncRNA.