Session Type: Abstract Submissions (ACR)
Background/Purpose: Scleroderma renal pathology is predominantly vascular and fibrotic without major inflammatory features. Accelerated hypertension and rapidly progressive renal dysfunction are hallmarks of scleroderma renal crisis. No current animal model of scleroderma (SSc) develops this complication. The TβRIIΔk-fib transgenic mouse model of SSc has a systemic vascular phenotype comprising hypertension and large vessel adventitial fibrosis without constitutive renal disease. However, the response to long-term further elevation of blood pressure or an inflammatory renal insult has not been studied. We have therefore explored the link between altered TGFb bioactivity, vasospasm and inflammatory stress on the systemic vascular endothelium using nitric oxide synthase inhibition and the nephrotoxic nephritis model using this strain.
Methods: Histological assessment of cardiac and renal architecture, immunostaining for microvessel density and inflammatory cells and assessment of microalbuminuria by ELISA were performed on adult male transgenic (TG) and littermate wildtype (WT) animals (n=6) treated with either the NO synthase inhibitor L-NAME for 20 weeks, or a single dose of nephrotoxic serum with pre-immunisation. Biochemical analysis of the TGFb signalling pathway was performed assessing RNA and protein using whole organ isolates, and by immunostaining of tissue sections. Results were compared to appropriate control groups.
Results: Increased cardiac mass, and an increase in cardiac collagen measured by qPCR and Sircol® assay in TG and WT treated groups demonstrated that L-NAME treatment successfully induced hypertensive stress in this strain. Whole kidney lysates from L-NAME treated TG animals showed upregulated expression of Col1a1 (TG untreated copy number 3937±315, TG treated 6319±48, p<0.05) and Pai-1 (TG untreated 410±57, TG treated 740±74, p<0.05), and glomerulosclerosis was present on sirius red staining in the TG treated group, suggesting that these animals exhibited an enhanced renal fibrotic response when compared to WT treated animals. No other structural vascular changes were identified. In contrast, by day 14, TG animals had developed significantly less proteinuria following treatment with nephrotoxic serum (NTS) when compared with WT littermates (figure 1). Examination of PAS stained samples showed increased severity and number of damaged glomeruli in WT treated mice compared with TG.
Conclusion: This mouse model of scleroderma demonstrates exaggerated fibrotic response to hypertensive injury and is relatively resistant to experimental glomerulonephritis. This is likely to be a consequence of increased tissue levels of TGFb. Both of these processes may underpin the unique vascular pathology seen in scleroderma renal crisis, this mouse strain provides a platform for further studies of renal injury in scleroderma.
D. J. Abraham,
M. A. Little,
C. P. Denton,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/perturbed-response-to-experimental-renal-injury-in-a-tgf%ce%b2-dependent-mouse-model-of-scleroderma/