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Biomarkers, genomics, proteomics, and gene regulation
Acquired Loss of Renal Nuclease Activity Is Restricted to DNaseI and Is an Organ-Selective Feature in Murine Lupus Nephritis

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An acquired loss of renal DNaseI promotes transformation of mild mesangial lupus nephritis into membranoproliferative end-stage organ disease. In this study, we analyzed expression profiles of DNaseI in other organs of lupus-prone (NZB×NZW)F1 mice during disease progression to determine whether silencing of the renal DNaseI gene is an organ-specific feature or whether loss of DNaseI reflects a systemic error in mice with sever lupus nephritis. The present results demonstrate normal or elevated levels of DNaseI mRNA and enzyme activity in liver, spleen, and serum samples from (NZB×NZW)F1 mice throughout all the stages of lupus nephritis. DNaseI activity was dramatically reduced only in kidneys of mice with sever nephritis and was the only nuclease that was down-regulated, whereas six other nucleases (DNaseII1 to 3, caspase-activated DNase, Dnase2a, and endonuclease G) were approximately normally expressed in kidneys, liver, and spleen. Loss of renal DNaseI was not accompanied by changes in serum DNaseI activity, suggesting independent mechanisms of DNaseI regulation in circulation and in kidneys and an absence of compensatory up-regulation of serum DNaseI activity in the case of renal DNaseI deficiency. Thus, silencing of renal DNaseI is a unique renal feature in membranoproliferative lupus nephritis. Determining the mechanism(s) responsible for DNaseI down-regulation might lead to the generation of new therapeutic targets to treat and prevent progressive lupus nephritis.

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Supported by the Foundation for Health and Rehabilitation through the Norwegian Rheumatology Organization (project 2004/2/0250), by the Northern Norway Regional Health Authority Medical Research Program (grants SFP-100-04 and SFP-101-04), and by the University of Tromsø as a milieu support (O.P.R.).

Supplemental material for this article can be found at http://ajp.amjpathol.org or at doi: 10.1016/j.ajpath.2011.05.011.