Renal Dnase1 Enzyme Activity and Protein Expression Is Selectively Shut Down in Murine and Human Membranoproliferative Lupus Nephritis

Anders A Tveita,Pierre Bobé,Svetlana N Zykova,Ole Petter Rekvig

doi:10.1371/journal.pone.0012096

Anders A Tveita, Pierre Bobé + Show 2 more

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https://doi.org/10.1371/journal.pone.0012096

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Abstract

BackgroundDeposition of chromatin-IgG complexes within glomerular membranes is a key event in the pathogenesis of lupus nephritis. We recently reported an acquired loss of renal Dnase1 expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase1 expression in lupus nephritis were analyzed.Methodology/Principal FindingsTotal nuclease activity and Dnase1 expression and activity was evaluated using in situ and in vitro analyses of kidneys and sera from (NZBxNZW)F1 mice of different ages, and from age-matched healthy controls. Immunofluorescence staining for Dnase1 was performed on kidney biopsies from (NZBxNZW)F1 mice as well as from human SLE patients and controls. Reduced serum Dnase1 activity was observed in both mesangial and end-stage lupus nephritis. A selective reduction in renal Dnase1 activity was seen in mice with massive deposition of chromatin-containing immune complexes in glomerular capillary walls. Mice with mild mesangial nephritis showed normal renal Dnase1 activity. Similar differences were seen when comparing human kidneys with severe and mild lupus nephritis. Dnase1 was diffusely expressed within the kidney in normal and mildly affected kidneys, whereas upon progression towards end-stage renal disease, Dnase1 was down-regulated in all renal compartments. This demonstrates that the changes associated with development of severe nephritis in the murine model are also relevant to human lupus nephritis.Conclusions/SignificanceReduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. Reduced Dnase1 activity reflects loss in the expression of the protein and not inhibition of enzyme activity.

Highlights

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the development of autoreactivity against nuclear antigens, including double-stranded DNA and histones [1,2,3]
We demonstrated that the appearance of anti-double-stranded DNA (dsDNA) antibodies in (NZBxNZW)F1 (B/ W) mice coincided with early signs of development of mesangial nephritis, while reduced renal Dnase1 mRNA expression correlated with progression of lupus nephritis into end-stage organ disease [32]
Characteristics of the experimental animals High anti-dsDNA antibody titer was present in all the animals with nephritis irrespective of age (26–38 w.o.) and was elevated for an average of 2 months prior to the development of overt proteinuria [34]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the development of autoreactivity against nuclear antigens, including double-stranded DNA (dsDNA) and histones [1,2,3]. DNA fragmentation by the activation of various nucleases is considered a key event in apoptotic cell death (reviewed in [11,12]). Increased levels of circulating DNA and nucleosomes have been reported in SLE [17,18,19], especially in active stages of the disease [20] and in lupus-prone mice [21]. We recently reported an acquired loss of renal Dnase expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase expression in lupus nephritis were analyzed

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