The Lymphatics in Kidney Health and Disease

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The Lymphatics in Kidney Health and Disease REVIEWS The lymphatics in kidney health and disease Michael D. Donnan 1,2, Yael Kenig- Kozlovsky3 and Susan E. Quaggin1,2 ✉ Abstract | The mammalian vascular system consists of two networks: the blood vascular system and the lymphatic vascular system. Throughout the body, the lymphatic system contributes to homeostatic mechanisms by draining extravasated interstitial fluid and facilitating the trafficking and activation of immune cells. In the kidney, lymphatic vessels exist mainly in the kidney cortex. In the medulla, the ascending vasa recta represent a hybrid lymphatic-like vessel that performs lymphatic- like roles in interstitial fluid reabsorption. Although the lymphatic network is mainly derived from the venous system, evidence supports the existence of lymphatic beds that are of non-venous origin. Following their development and maturation, lymphatic vessel density remains relatively stable; however, these vessels undergo dynamic functional changes to meet tissue demands. Additionally, new lymphatic growth, or lymphangiogenesis, can be induced by pathological conditions such as tissue injury, interstitial fluid overload, hyperglycaemia and inflammation. Lymphangiogenesis is also associated with conditions such as polycystic kidney disease, hypertension, ultrafiltration failure and transplant rejection. Although lymphangiogenesis has protective functions in clearing accumulated fluid and immune cells, the kidney lymphatics may also propagate an inflammatory feedback loop, exacerbating inflammation and fibrosis. Greater understanding of lymphatic biology, including the developmental origin and function of the lymphatics and their response to pathogenic stimuli, may aid the development of new therapeutic agents that target the lymphatic system. In mammals, the circulatory system consists of the blood role of dermal lymphatics in fluid homeostasis4 and the and the lymphatic vascular systems, which perform contribution of cardiac lymphatic remodelling to cardio- complementary roles in maintaining body homeostasis. vascular disease and atherosclerosis5. These studies have In contrast to the continuous arterial to venous circuit of also led to the identification and characterization of lym- the blood vascular system, the lymphatic system consists phatic vessels in tissues previously thought to be devoid of a blind-ended network of vessels, which provides uni- of lymphatics. For example, the discovery of meningeal directional, low- flow, transport from peripheral tissues lymphatics in the central nervous system has redefined towards the central venous system. This network trans- our understanding of how the brain responds to inflam- ports interstitial fluid, immune cells, antigens, lipids mation and degeneration6. Hybrid lymphatic-like vessels and associated macromolecules — collectively known have also been discovered in multiple tissues through- 1Feinberg Cardiovascular & as lymph — which is integral to the maintenance of body out the body, including the Schlemm’s canal in the eye7, Renal Research Institute, fluid homeostasis, immune cell trafficking, inflamma- the spiral arteries in the placenta8 and the ascending Northwestern University 1 9 Feinberg School of Medicine, tion and regulation of blood pressure . Despite intensive vasa recta (AVR) within the kidney . In this Review, we Chicago, IL, USA. efforts to extensively detail the blood vascular system discuss the origins and organization of the lymphatic 2Division of Nephrology & in development and disease, the lymphatic system has system and hybrid lymphatic- like vessels, their role in Hypertension, Northwestern historically been overlooked, in part owing to difficulty kidney function and disease and the potential role of the University Feinberg School of in visualizing the typically small and sparse lymphatic lymphatic system as a therapeutic target. Medicine, Chicago, IL, USA. vessels. However, advances in imaging and genetic 3 Department of Nephrology technologies have accelerated our understanding of the Lymphatic structure and organization & Hypertension, Rambam Medical Center, Haifa, Israel. specialized functions of the lymphatic vascular system. The lymphatic system comprises lymphatic vessels, lym- ✉e- mail: quaggin@ These studies have provided insights into unique char- phoid tissues and lymphoid organs that exist through- northwestern.edu acteristics of many organ- specific lymphatic systems, out the body (FIG. 1). A network of highly branched, https://doi.org/10.1038/ including structural characteristics of the intestinal lacte- blind- ended lymphatic capillaries spans almost every s41581-021-00438- y als that underlie their ability to absorb dietary fats2,3, the vascularized tissue, and enables uptake of surrounding NATURE REVIEWS | NEPHROLOGY VOLUME 17 | OCTOBER 2021 | 655 0123456789();: REVIEWS Key points lymphatic vasculature are not uniform throughout the body and may differ between species. For example, • Advances in imaging and genetics technologies have furthered our understanding of the collecting lymphatics of the mouse lung are devoid the role of lymphatic vascular systems in both homeostasis and disease. of smooth muscle cells and fluid flow relies on changes • Key advances include the discovery of hybrid lymphatic-like vessels in multiple tissues in respiratory pressures13, whereas lymphatic flow in the including in the kidney, where the ascending vasa recta express a combination of lungs of sheep seems to be regulated by intrinsic lym- both blood and lymphatic endothelial markers and perform a lymphatic- like role in phatic pumping in addition to passive factors14. These reabsorbing interstitial fluid in the medulla. differences underscore the organ and species- specific • Kidney lymphangiogenesis is strongly associated with injury, inflammation and the heterogeneity of lymphatics. progression of fibrosis. Peripheral lymphatic vessels direct antigen and • Lymphangiogenesis can perform a protective role in clearing the accumulated fluid immune cell- containing lymph towards local draining and immune cells associated with inflammation from the interstitial space; however, 15 the kidney lymphatics also function to propagate an inflammatory feedback loop in lymph nodes (DLNs) . Over 200 DLNs exist throughout coordination with the draining lymph nodes, which may exacerbate inflammation and the human body, the development of which is closely fibrosis. In addition, chronic inflammation can result in the disorganized growth of aligned with those of lymphatic vessels. Within the leaky, poorly functioning lymphatic vessels, further contributing to tissue injury. DLNs, cytokines, immune cells and antigens interact • Targeting the lymphatic system is a potential future direction for new therapeutics with native dendritic cells and recruited leukocytes for kidney disease, and several therapies are undergoing investigation in preclinical within highly specialized lymph node compartments, models. allowing selective filtration of these inflammatory cells • Better understanding of the context- dependent consequences of kidney and molecules, and enabling modulation of the immune lymphangiogenesis, as well as the mechanisms of action and potential off-target response16,17. Lymph then continues through these DLNs consequences of targeting the proposed molecular pathways are needed prior to into larger lymphatic ducts, including the thoracic their clinical use. duct, which eventually returns the lymph to the central circulation18. interstitial fluid and immune cells. Similar to other Lymphatic development and function capillary structures, a single layer of endothelial cells A variety of signalling molecules and pathways coordi- forms the innermost layer of the lymphatic vasculature. nate the development and remodelling of the lymphatic However, in contrast to blood endothelial cells (BECs), vasculature. Several of these pathways are also involved lymphatic endothelial cells (LECs) exhibit unique inter- in development of the blood vasculature; however, spe- cellular junctions that enable enhanced reabsorption cific factors contribute to the determination of the fate of fluid and molecules. In the blind- ended initial lym- of LECs (Table 1). As described below, these unique fac- phatic capillaries, discontinuous, punctate, button- like tors can help to distinguish lymphatic endothelium from junctions anchor the sides of overlapping flaps of oak blood vascular endothelium, and can be used to identify leaf- shaped LECs. Together with the thin, discontinu- potential hybrid structures. ous basement membrane of the lymphatic capillaries and absence of supporting mural cells, these specialized Transcription factors. Prospero- related homeobox junctions are integral to the high permeability of lym- transcription factor 1 (PROX-1) is considered to be phatic capillaries and allow the uptake of fluid and cells the master regulator of lymphatic fate specification. from the surrounding tissues. Loss of these button-like It is expressed by all LECs and is required for their ini- junctions results in impaired capillary permeability and tial differentiation. In mice, PROX-1 is expressed from disruption of fluid uptake2. embryonic day (E) 9.5 by endothelial cells in the ante- The lymphatic capillaries converge towards progres- rior side of the cardinal vein, which give rise to LEC sively larger and fewer collecting lymphatic vessels. The progenitors19. Downregulation of Prox-1 at any stage LECs in collector vessels become more elongated, and during development will induce
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