Using polycystic kidney disease to understand cilium mediated endogenous repair and bone marrow mediated exogenous repair
Creators: name: Verghese, Elizabeth
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: The kidney has an incredible ability to repair after renal injury. The studies in this thesis aim to use the current understanding of aberrant repair in the form of Polycystic kidney disease (PKD) to investigate the contribution of somatic renal epithelial cells and bone marrow derived cells to renal repair. Defects in the renal cilium, a non-motile hair like structure, present on renal epithelial cells, play a central role in the pathogenesis of errant repair in the form of PKD. The current studies demonstrate for the first time that the renal cilium could play a critical role in repair in a mouse model of ischaemic injury by mediating the restoration of the injured proximal tubule epithelium and preventing injury-induced de-differentiation throughout the nephron. The results show that 4 days post ischaemic injury, an apical cilium is present on the flat dedifferentiated mesenchymal cells that repopulate the denuded proximal tubule. These findings suggest that the renal cilium may have roles in establishing cell polarity, orientating cell division and cell differentiation. One week after ischaemic injury, cilium length increased dramatically throughout the nephron and then returned to normal 6 weeks post injury when structural repair was evident. Our studies in biopsy series from human allografts with acute tubular necrosis demonstrated that the findings in the mice were a clinically relevant phenomenon. The ATN affect allografts showed cilium elongation approximately 1 week post injury followed by cilium length normalization that coincided with functional repair. Our in vitro studies demonstrated that cilium elongation is driven by hypoxia simulated by the upregulation of hypoxia inducible factor alpha (HIFα) due to the addition of Cobalt Chloride. We propose that HIFα mediated cilium elongation increases cilium based signaling which counteracts the natural propensity of the epithelium to undergo de-differentiation in response to hypoxia and cilium length returns to normal upon the completion of the repair. The cystic phenotype of PKD cells was used as a marker to amplify and identify the rare contribution of bone marrow (BM)-derived cells to the renal epithelium during renal regeneration. In PKD, cystogenesis may arise from the clonal proliferation of a small collection of mutant cells. The current study investigated why PKD does not recur in transplanted kidneys of PKD patients, despite the reported potential of BM derived cells to give rise to renal epithelium. In a mouse model that paralleled human transplantation, confocal microscopy and 3D reconstructions showed that BM-derived cells present in the kidney did not exhibit characteristics of renal tubular epithelial cells including the proliferative phenotype associated with PKD. The absence of BM-derived renal epithelial cells in our study could explains why cystogenesis does not occur in transplanted kidneys and illustrates the potential difficulties of replacing injured tubular epithelium with BM-renal epithelium. Our findings suggest that cilium mediated endogenous repair shows more therapeutic potential than the replacement of injured renal epithelium by bone marrow derived cells. The renal cilium is a clinical indicator of renal repair and more importantly a possible mediator of renal repair. A better understanding of cilium based signaling in renal repair could provide novel therapeutic targets for both acute tubular necrosis and polycystic kidney disease.