The Kidney Lymphatic Vasculature: Development, Cellular Origins and Implications for Renal Diseases

Lymphatic vasculature, appreciated as a conduit for the clearance of tissue fluid, macromolecules and immune cell from tissues, is a promising target for therapeutic intervention in diseases including neurodegeneration, cardiovascular disease and cancer. Whereas studies of mouse embryos demonstrate these vessels assemble via diverse cellular mechanisms from several cellular origins, studies in mouse models of disease highlight distinct roles of lymphatics in the modulation of immunity. Despite these findings, little is known about lymphatics in development or disease of the kidney, an organ vital for waste excretion whilst maintaining fluid, electrolyte and endocrine homeostasis. The aim of this thesis was to study the development, cellular origins and structural and molecular profile of kidney lymphatics in renal health and disease. Firstly, wholemount immunohistochemistry, tissue clearing and three- dimensional imaging was used to conceive a spatial and quantitative timeline describing mammalian kidney lymphatic development, whilst identifying structural defects of kidney lymphatic in the early stages of murine polycystic kidney disease. Secondly, the cellular origins of kidney lymphatics were deciphered using Cre recombinase technology in mouse, providing evidence that 14-15% of kidney lymphatics arise from a lineage shared by differentiated renal cell types. Finally, three-dimensional imaging and single-cell RNA sequencing were applied to non-transplanted human kidneys or those with chronic transplant rejection. Chronic transplant rejection was associated with an expansion of kidney lymphatics and their infiltration into the medulla, a region of the kidney which is devoid of lymphatics in health. Further, the lymphatics of rejecting kidneys adopted an immunoregulatory profile, implicating these vessels in transplant longevity and allograft rejection. This thesis presents insights into when and how kidney lymphatics develop and implicate structural or molecular changes to these vessels as features of polycystic kidney disease and chronic transplant rejection. These findings inform future studies targeting and exploiting kidney lymphatics in renal development and disease