The role of microRNAs and human epidermal growth factor receptor 2 in proliferative lupus nephritis

Patrícia Costa-Reis, Pierre A. Russo, Zhe Zhang, Lucrezia Colonna, Kelly Maurer, Stefania Gallucci, Steffan W. Schulz, Adnan N. Kiani, Michelle Petri, Kathleen E. Sullivan

Research output: Contribution to journalArticlepeer-review

Abstract

Objective To understand the roles of microRNAs (miRNAs) in proliferative lupus nephritis (LN). Methods A high-throughput analysis of the miRNA pattern of the kidneys of LN patients and controls was performed by molecular digital detection. Urinary miRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target gene expression in human mesangial cells was evaluated by arrays and qRT-PCR. Human epidermal growth factor receptor 2 (HER-2) was analyzed by immunohistochemistry in kidney samples from LN patients and in a murine model of lupus. Urinary levels of HER-2, monocyte chemotactic protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured by enzyme-linked immunosorbent assay. Results Levels of the miRNAs miR-26a and miR-30b were decreased in the kidneys and urine of LN patients. In vitro these miRNAs controlled mesangial cell proliferation, and their expression was regulated by HER-2. HER-2 was overexpressed in lupus-prone NZM2410 mice and in the kidneys of patients with LN, but not in other mesangioproliferative glomerulonephritides. HER-2 was found to be up-regulated by interferon-α and interferon regulatory factor 1. Urinary HER-2 was increased in LN and reflected disease activity, and its levels correlated with those of 2 other recognized LN biomarkers, MCP-1 and VCAM-1. Conclusion The kidney miRNA pattern is broadly altered in LN, which contributes to uncontrolled cell proliferation. Levels of the miRNAs miR-26a and miR-30b are decreased in the kidneys and urine of LN patients, and they directly regulate the cell cycle in mesangial cells. The levels of these miRNAs are controlled by HER-2, which is overexpressed in NZM2410 mice and in the kidneys and urine of LN patients. HER-2, miR-26a, and miR-30b are thus potential LN biomarkers, and blocking HER-2 may be a promising new strategy to decrease cell proliferation and damage in this disease.

Original languageEnglish (US)
Pages (from-to)2415-2426
Number of pages12
JournalArthritis and Rheumatology
Volume67
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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