Downregulated expression in high IgA (HIGA) mice and the renal protective role of meprinbeta.

Abstract

This study discusses the critical role of the metalloproteinase meprinbeta in the progression of glomerulonephritis. Using a microarray technique, the gene expression profiles in glomeruli isolated from high serum IgA (HIGA) mice with a purity of 97% or greater were examined. HIGA mice are a valid model of human IgA nephropathy (IgAN), with the typical pathological features of this condition, including a consistently high serum IgA level as well as dominant mesangial IgA deposition and mesangial enlargement. Among the many upregulated/downregulated genes after the development of IgAN, the downregulation of meprinbeta was intriguing. The expression level of the meprinbeta gene at 40 weeks of age was 52% of that observed at 8 weeks of age (prior to the development of IgAN), although in the control BALB/c mice, a 2.19-fold elevation was seen. These results were also confirmed by semi-quantitative RT-PCR and immunostaining analyses. As meprinbeta is a subunit of metalloproteinase meprins (meprin A, meprin B) and meprins are capable of proteolytically degrading extracellular matrix (ECM) components and proteolytically processing bioactive peptides, the downregulation of meprinbeta may contribute to the progression of glomerulonephritis and the eventual glomerular scarring. This working hypothesis was examined using an in vivo meprinbeta inhibition study. The inhibition of meprins by actinonin exacerbated some parameters of renal injury in mice afflicted with anti-glomerular basement membrane (anti-GBM) antibody-associated nephritis. These in vitro and in vivo results suggest that meprinbeta may play a protective role against the progression of renal injury through the degradation of ECM and bioactive peptides.

• Authors: Hiromitsu Yoshimura, Masayoshi Ito, Yusuke Kuwahara, Aiko Ishii, Katsuki Tsuritani, Atsushi Nakamura, Yasushi Hirasawa, Tadashi Nagamatsu
• Journal: Life sciences (Life Sci) Vol. 82 Issue 15-16 Pg. 899-908 (Apr 09 2008) ISSN: 0024-3205 [Print] Netherlands
• PMID: 18355876 (Publication Type: Journal Article)

Chemical References

• Hydroxamic Acids
• Immunoglobulin A
• Metalloendopeptidases
• meprin A
• actinonin

Topics

• Animals
• Anti-Glomerular Basement Membrane Disease (genetics, pathology)
• Body Weight (genetics, physiology)
• Disease Progression
• Down-Regulation (physiology)
• Female
• Gene Expression Profiling
• Hydroxamic Acids (pharmacology)
• Immunoglobulin A (biosynthesis, blood, genetics)
• Immunohistochemistry
• Kidney (pathology)
• Kidney Glomerulus (pathology)
• Metalloendopeptidases (genetics, physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Proteinuria (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Urodynamics (genetics, physiology)