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41 Relevance of mouse lupus models of lupus nephritis to progression of ckd
  1. CC Berthier1,
  2. M Kretzler1 and
  3. A Davidson2
  1. 1University of Michigan, Internal Medicine, Ann Arbour, USA
  2. 2Feinstein Institute for Medical Research, Centre for Autoimmunity and Musculoskeletal Diseases, Manhasset- NY, USA

Abstract

Background and aims Risk for progression of CKD in humans is associated with an interstitial molecular signature containing 68 genes. Of these, a decrease in renal expression of EGF with a concomitant increase in urinary EGF improves the ability to predict CKD expression.

Methods To determine whether these 68 genes can be used in pre-clinical studies to model disease and therapeutic responses, we analysed microarray data of kidneys from three mouse lupus strains at various disease stages and after remission induction. Renal macrophage gene expression was assessed using RNASeq.

Results 61/64 genes have mouse gene IDs and are represented on the mouse microarray chip. Of these 49 were regulated in the same direction as in humans in at least one mouse strain with 28 common to all three strains. 9/61 genes, including EGF and TIMP1 only became abnormally regulated during established disease or during complete proteinuric relapse, confirming their association with CKD progression. Renal C1qa is a CKD marker produced mainly by renal macrophages but has a similarly high expression level in isolated pre-nephritis and nephritic renal macrophages. It can therefore be used as a biomarker of increased macrophage infiltration, a known poor prognostic feature in human lupus nephritis.

Conclusions Mice with lupus nephritis have a similar pattern of CKD-related gene expression to humans and these genes can be used to track therapeutic responses. Downregulation of EGF and upregulation of TIMP1 indicate progressive disease and C1qa can be used as a marker of macrophage infiltration. The fibrosis signature is best modelled in NZW/BXSB mice.

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