Session Title: Pediatric Rheumatology - Pathogenesis and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: microRNAS (miRNAs) are noncoding RNAs responsible for post-transcriptional gene silencing. These key regulatory molecules control the expression of multiple genes, so its dysregulation can contribute to sustained pathology. Our goal was to study the miRNA pattern of lupus nephritis (LN) in order to better understand its pathogenesis and to identify clinically relevant pathways.
Methods: RNA was extracted from paraffin embedded kidney samples of controls (n=6) and patients with LN (n=18) and post-streptococcal glomerulonephritis (n=2). Molecular digital detection of miRNAs was performed, analyzed on R, and confirmed by qRT-PCR. Gene expression of human kidney cells lines, submitted to knockdowns of the miRNAs of interest using lentivirus, was studied with GeneChip® 2.0 ST Arrays. Off-target lentivirus were used as controls. Immunohistochemistry, immunofluorescence and western-blots for HER2 were performed.
Results: There was a kidney LN specific miRNA signature, which, according to IPA® pathway analysis, mainly reflected cell proliferation and inflammation. miR-26a and miR-30b were found to be significantly decreased in LN (p=0.002; p=0.008, respectively). Furthermore, miR -26a levels inversely correlated with proteinuria (p=0.005), casts (p=0.031) and the presence of crescents (p=0.030), a sign of kidney cell proliferation. PPARCG1A, which is involved in type 1 interferon pathway, was found to be highly increased in mesangial cells submitted to miR-26a knock-down. Finally, HER2, a protein that regulates miR-26a and miR-30b levels in breast cancer cell lines, was found to be highly increased in the glomeruli and tubular compartments of LN patients. HER2 was found to be expressed in human podocytes, tubular and mesangial cell lines and its expression was increased by α –interferon (p=0.002).
Conclusion: The kidneys of LN patients have a specific miRNA pattern, characterized by a significant decrease of miR-26a and miR-30b. These miRNAs were previously found to be key regulators of cell proliferation in several malignancies and miR-26a was found to reduce cancer cell progression and cause tumor-specific apoptosis in vivo. Our data indicate that these miRNAs also regulate cell proliferation in LN. Interestingly, it was previously shown that trastuzumab, a monoclonal antibody against HER2, produces therapeutic actions by up-regulating miR-26a and miR-30b in breast cancer cell lines. Since we demonstrated that HER2 was highly increased in the kidneys of LN patients, blocking HER2 with trastuzumab may be a new promising pathway to decrease cell proliferation and damage in this disease. miR-26a, miR-30b and HER2 are, therefore, three new interesting players on LN pathogenesis.
K. E. Sullivan,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mir-26a-mir-30b-and-her2-new-players-on-lupus-nephritis-pathogenesis/