Micro-RNA analysis of renal biopsies in human lupus nephritis demonstrates up-regulated miR-422a driving reduction of kallikrein-related peptidase 4

Eleni Krasoudaki, Aggelos Banos, Elias Stagakis, Konstantinos Loupasakis, Elias Drakos, Vaios Sinatkas, Amalia Zampoulaki, Aikaterini Papagianni, Dimitrios Iliopoulos, Dimitrios T. Boumpas, George K. Bertsias

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

BackgroundAberrancies 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). MethodsKidney 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. ResultsTwenty-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. ConclusionsKLK4, 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.

Original languageEnglish (US)
Pages (from-to)1676-1686
Number of pages11
JournalNephrology Dialysis Transplantation
Volume31
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Keywords

  • autoimmune
  • epigenetic
  • glomerulonephritis
  • inflammation
  • tissue injury

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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