Analysis of the role and regulation of disintegrin metalloproteases in renal fibrosis

Chronic Kidney Disease (CKD) affects about 10-20% of the adult population of the developed world. The underlying molecular mechanisms contributing to its varied pathophysiology CKD are still unclear. Without early diagnosis and therapeutic intervention, patients with CKD risk progressing to end stage renal failure (ESRF) requiring renal replacement therapy such as dialysis and eventually a renal transplant. Tubulointerstitial fibrosis is the common end point in most progressive renal diseases and has consistently been shown to be the best histological predictor of progression towards end stage renal failure. This 'point of no return' involves atrophy of the tubulointerstitium, leukocyte infiltration, persistent fibroblast proliferation and activation and dysregulation of extracellular matrix (ECM) resulting ultimately in scarring and loss of function. TGFB initiates and is involved in the entire course of fibrosis pathogenesis. Critical mediators of TGFB regulation are the intracellular signal transducers - the Smads which regulate gene transcription, and the recently discovered small neucleotide RNAs - microRNAs (miRs). miRs are a post transcriptional gene regulatory system and demonstrate distinct spatio-temporal expression and their expression is associated with crucial developmental and pathophysiological processes. Disintegrin metalloproteases (ADAMs) are members of the calss of zinc-ion proteases that can regulate key cellular and acellular processes including chemotaxis, adhesion and fusion, and modulate auto and paracrine signalling pathways by regulating ligand/receptor availability. Therefore, ADAMs can potentially regulate both inflammatory and fibrotic changes associated with renal disease. However, evidence towards the role of ADAMs in renal disease remains largely descriptive. While TGFB regulation of MMPs and TIMPs in renal disease has been well studies, the regulation or mechanisms of action of ADAMs in renal disease remains unknown. This thesis aims to demonstrate the involvement of proteolytically active ADAMs in renal fibrosis and provide mechanistic evidence towards transcriptional and post-transcriptional regulation of these ADAMs by canonical TGFB signalling