miR-21 Promotes Fibrogenesis in Peritoneal Dialysis

Abstract

Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.

Biogenesis, Stabilization, and Transport of microRNAs in Kidney Health and Disease

“…Our laboratory is investigating the use of miRNAs in urine and other body fluids as kidney disease biomarkers [14,18,19,20,34,80,81,82]. On the basis of the above studies, we analyzed human urine for presence on EVA and non-EVA-miRNAs [69].…”

miR-200c Prevents TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Fibrogenesis in Mesothelial Cells by Targeting ZEB2 and Notch1

“…Other investigators have reported miR-200c expression in dialysate-derived mesothelial cells, which decreased with increasing time on PD, 44 but in another study, investigators using a hybridization array found low signal intensity of miR-200c expression in omentum-derived mesothelial cells that did not change upon stimulation with TGF-β1 12 . The discrepant findings may be related to the source of mesothelial cells used in the experiments, the dose of TGF-β1, and the methods used to detect miRs.…”

“…Dysregulated miR expression has been observed in pathological conditions, such as cancer and tissue fibrosis, and several miRs have been implicated in the regulation of EMT transcription factors, resulting in repression or promotion of EMT and fibrosis. In this respect, miR-21 has been shown to promote peritoneal fibrosis,12, 13 whereas miR-15a-5p, miR-30a, miR-129-5p, and miR-302c have been shown to suppress peritoneal fibrosis 14, 15, 16, 17…”

Increased miR-7641 Levels in Peritoneal Hyalinizing Vasculopathy in Long-Term Peritoneal Dialysis Patients

“…These data confirm previous observations from our group, where biocompatible low-GDP PDFs preserved the mesothelial monolayer and vessel wall integrity better than conventional ones [ 14 ]. Accordingly, peritoneal morphological changes, including PHV, are aggravated with long-term PD [ 17 , 37 , 38 ]. Interestingly, microvascular system alterations of diabetes mellitus patients were associated with increased type IV collagen biosynthesis, both at gene and protein level, and posttranslational alterations were detected, especially glycation, leading to advanced glycation end-products (AGEs) and collagen covalent crosslinks.…”