Russell, Lauren Grace; (2024) Indian Hedgehog in Kidney Development and Polycystic Kidney Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hedgehog (Hh) signalling is critical in kidney development and has also been implicated in polycystic kidney disease (PKD), the leading genetic cause of renal disease. Indian hedgehog (Ihh) is one of three ligands that activates the Hh pathway and has been implicated as having a role in cyst formation. However, the localisation and functional role of Ihh in either kidney development or PKD is not yet understood, and this was explored in my thesis. Utilising scRNA-seq datasets, wholemount fluorescence in situ hybridisation and immunolabelling, I demonstrated Ihh expression in the maturing proximal tubules of the mouse embryonic kidney. Renal developmental defects were found in both a global Ihh knockout model and a model of conditional deletion of Ihh within the developing kidney. The conditional deletion of Ihh resulted in smaller kidneys alongside reduced numbers of nephron progenitor cells, early nephrogenic structures, and glomeruli. In the Cpk mouse model of Autosomal Recessive PKD (ARPKD), Ihh transcript levels were unaltered. In contrast, elevated levels of Gli3, a downstream effector of the Hh pathway were found; an observation replicated in a clinically relevant human cellular model of ARPKD. However, haploinsufficiency of Gli3 had no effect on disease progression in Cpk mice. Similarly, there was no effect of GLI3 downregulation on cyst size in the human cellular ARPKD model. In conclusion, Ihh plays a role in the processes underlying nephron formation, mechanisms that can give rise to low nephron endowment in humans, which is associated with chronic kidney disease (CKD) in later life. In ARPKD, Gli3, but not Ihh, is upregulated. However, Gli3 downregulation in both animal and human cellular ARPKD models had no effect on the progression of cystic disease.

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