Abstract
Overview: Vasculitis is an autoimmune disease characterised by the swelling and inflammation of blood vessels. Renal vasculitis is a rare, yet severe disease characterised by the inflammation of glomeruli and affiliated tubular atrophy. Commonly associated with antineutrophil cytoplasmic autoantibodies (ANCA), the term renal vasculitis is frequently interchangeable with ANCA-associated vasculitis (AAV). Emerging evidence has demonstrated that the degree of AAV-related tubular atrophy may predict patient outcome, however the precise molecular mechanism remains unclear. Tumour protein 53 (p53) is a canonical tumour suppressor protein that can play a pathological role by initiating unwanted apoptosis and cellular arrest of non-malignant cells. Isoforms of p53 exist, and one of these (∆133p53) can promote inflammation. This study aimed to elucidate if two forms of p53 (∆133p53 and wild-type p53) were increased in renal vasculitis. Additionally, if p53 forms were associated with tubular atrophy or inflammation that contributes to disease progression. Furthermore, this study aimed to correlate the observed p53 expression to characteristic patient immunopathological groupings found as part of a previous study.
Hypothesis: Wild-type p53 (WTp53) and ∆133p53 will be aberrantly expressed in AAV-tissue. Additionally, p53 expression will be associated with a specific AAV patient immunopathological grouping.
Methods: Formalin fixed renal biopsy samples (N = 20) diagnosed with AAV from patients attending Dunedin Hospital were qualitatively analysed for ∆133p53 and functional WTp53 using RNAscope® and immunohistochemistry protocols, respectively. Following this, visualised p53 expression was quantitated and subsequently correlated to previously characterised patient immunopathological groupings.
Results: ∆133p53 was not present across all AAV tissue biopsy samples. However, WTp53 was expressed predominantly in the renal tubular epithelial cells. The presence of functional WTp53 was further confirmed by the presence of p21, a downstream effector of WTp53. Quantitative analyses of WTp53/p21 elucidated that increased tubular expression of functional WTp53 was significantly associated with an elevated Th17 immunopathological phenotype. However, further studies and a larger cohort size are required to validate this finding.
Conclusion: AAV tissue possessing a marked Th17 immunopathological phenotype concurrently express elevated levels of functionally active WTp53, almost exclusively in the kidney tubules. This finding suggests a role for Th17-mediated, WTp53 in the pathogenesis of AAV-related tubular atrophy.