Micro-RNA analysis of renal biopsies in human lupus nephritis demonstrates up-regulated miR-422a driving reduction of kallikrein-related peptidase 4.
Title | Micro-RNA analysis of renal biopsies in human lupus nephritis demonstrates up-regulated miR-422a driving reduction of kallikrein-related peptidase 4. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Krasoudaki, E., Banos A., Stagakis E., Loupasakis K., Drakos E., Sinatkas V., Zampoulaki A., Papagianni A., Iliopoulos D., Boumpas D. T., & Bertsias G. K. |
Journal | Nephrol Dial Transplant |
Date Published | 2015 Nov 5 |
ISSN | 1460-2385 |
Abstract | BACKGROUND: Aberrancies in gene expression in immune effector cells and in end-organs are implicated in lupus pathogenesis. To gain insights into the mechanisms of tissue injury, we profiled the expression of micro-RNAs in inflammatory kidney lesions of human lupus nephritis (LN).METHODS: Kidney specimens were from patients with active proliferative, membranous or mixed LN and unaffected control tissue. Micro-RNAs were quantified by TaqMan Low Density Arrays. Bioinformatics was employed to predict gene targets, gene networks and perturbed signaling pathways. Results were validated by transfection studies (luciferase assay, real-time PCR) and in murine LN. Protein expression was determined by immunoblotting and immunohistochemistry.RESULTS: Twenty-four micro-RNAs were dysregulated (9 up-regulated, 15 down-regulated) in human LN compared with control renal tissue. Their predicted gene targets participated in pathways associated with TGF-β, kinases, NF-κB, HNF4A, Wnt/β-catenin, STAT3 and IL-4. miR-422a showed the highest upregulation (17-fold) in active LN and correlated with fibrinoid necrosis lesions (β = 0.63, P = 0.002). In transfection studies, miR-422a was found to directly target kallikrein-related peptidase 4 (KLK4) mRNA. Concordantly, KLK4 mRNA was significantly reduced in the kidneys of human and murine LN and correlated inversely with miR-422a levels. Immunohistochemistry confirmed reduced KLK4 protein expression in renal mesangial and tubular epithelial cells in human and murine LN.CONCLUSIONS: KLK4, a serine esterase with putative renoprotective properties, is down-regulated by miR-422a in LN kidney suggesting that, in addition to immune activation, local factors may be implicated in the disease. |
DOI | 10.1093/ndt/gfv374 |
Alternate Journal | Nephrol. Dial. Transplant. |
PubMed ID | 26546590 |