The Role of MicroRNAs and Human Epidermal Growth Factor Receptor 2 in Proliferative Lupus Nephritis

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.