Acquired loss of renal nuclease activity is restricted to DNase I and is an organselective feature in murine lupus nephritis

Abstract

An acquired loss of renal DNaseI has recently been shown to promote transformation of mild mesangial lupus nephritis into membrano-proliferative end-stage organ disease. In this study, we analyzed expression profiles of DNaseI in other organs of lupus-prone (NZBxNZW)F1 mice during disease progression to determine if silencing of the renal DNaseI gene is an organ specific feature or if loss of DNaseI reflects a systemic error in mice with sever lupus nephritis. Our results demonstrate normal or elevated levels of DNaseI mRNA and enzyme activity in liver, spleen and serum samples of (NZBxNZW)F1 mice throughout all 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, while 6 other nucleases (DNaseIl1-3, caspase activated deoxyribonuclease, Dnase2a, and endonuclease G) were largely normally expressed in kidneys, liver and spleen. Loss of renal DNaseI was not accompanied by changes in serum DNaseI activity, suggesting an independent mechanism of DNaseI regulation in circulation and in kidneys, and an absence of compensatory upregulation of serum DNaseI activity in case of renal DNaseI deficiency. Thus, silencing of renal DNaseI is a unique renal feature in membrano-proliferative lupus nephritis. Determination of mechanism(s) responsible for DNaseI down-regulation is a future step in generation of new therapeutic targets to treat and prevent progressive lupus nephritis.