Lymphangiogenesis and Lymphatic Barrier Dysfunction in Renal Fibrosis

Abstract

As an integral part of the vascular system, the lymphatic vasculature is essential for tissue fluid homeostasis, nutritional lipid assimilation and immune regulation. The composition of the lymphatic vasculature includes fluid-absorbing initial lymphatic vessels (LVs), transporting collecting vessels and anti-regurgitation valves. Although, in recent decades, research has drastically enlightened our view of LVs, investigations of initial LVs, also known as lymphatic capillaries, have been stagnant due to technical limitations. In the kidney, the lymphatic vasculature mainly presents in the cortex, keeping the local balance of fluid, solutes and immune cells. The contribution of renal LVs to various forms of pathology, especially chronic kidney diseases, has been addressed in previous studies, however with diverging and inconclusive results. In this review, we discuss the most recent advances in the proliferation and permeability of lymphatic capillaries as well as their influencing factors. Novel technologies to visualize and measure LVs function are described. Then, we highlight the role of the lymphatic network in renal fibrosis and the crosstalk between kidney and other organs, such as gut and heart.

Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

“…[86][87][88][89] Together with soluble factors, tissue stiffening produces pathological vasculature with altered lymph fluid flow characteristics and transmural transport properties that maintain or worsen the disease state. [8][9][10][11]76,77,80] Moreover, increased lymphatic vascularization can promote fibrosis via a positive feedback loop, [12,23,83,[90][91][92] and when rapid lymphangiogenesis occurs, vascular permeability (i.e., barrier function) can increase [21,23,93] and produce leaky, nonfunctional vessels. [29,87,94] Conversely, there are disease states with significant fibrosis (e.g., secondary lymphedema, myocardial edema) and insufficient lymphatic vasculature (i.e., inadequate growth, low number of vessels, low vessel function).…”

“…[26][27][28] In chronic kidney disease with renal fibrosis, increased lymphangiogenesis helps drain excess fluid, but increased recruitment of dendritic cells to the lymph nodes combined with leaky vessels disrupts the immune response. [10,13] Since inflammation and tissue stiffening can trigger lymphangiogenesis and alter barrier function, [14,16,20,29,30] studies on lymphatic vasculature should consider each of these factors when developing therapeutic strategies. Currently, there are differences in treatment approaches based on the type of lymphatic dysregulation.…”

“…[ 26–28 ] In chronic kidney disease with renal fibrosis, increased lymphangiogenesis helps drain excess fluid, but increased recruitment of dendritic cells to the lymph nodes combined with leaky vessels disrupts the immune response. [ 10,13 ]…”

“…[7] Fibrosis-excess extracellular matrix (ECM) deposition and scarring of connective tissue-is a common occurrence across numerous pathological conditions that also involve significant amount of lymphatic dysregulation (e.g., chronic kidney disease, lymphedema, cardiac fibrosis, cancerous tumors). [8][9][10][11][12][13] Inflammation often works in tandem with fibrosis in many conditions to create a biophysical (e.g., ECM stiffening), biomechanical (e.g., increased interstitial pressure), and biochemical (e.g., pro-lymphangiogenic growth factors, inflammatory cytokines) environment that changes with time and perpetuates the disease state. [8,[14][15][16][17][18] These changes not only influence lymphatic endothelial cell (LEC) behavior (i.e., proliferation, migration) and cell-cell junction integrity, [2,19,20] but they also affect stromal cell populations (e.g., fibroblasts, immune cells) that interact with LECs through paracrine signaling.…”

“…Adv. Biology 2023,7, 2200158 • Excess lymphatic growth in response to fibrosis can cause organ function disruption (e.g., kidney ultrafiltration) • Aberrant mural cell recruitment causes vascular remodeling of the lymphatic tissue • Lymphatic vasculature recruits immune cells, aggravating the inflammatory response and further progressing fibrosis[4,10,82,125] …”