CD137L-macrophage induce lymphatic endothelial cells autophagy to promote lymphangiogenesis in renal fibrosis

Abstract

Renal lymphangiogenesis is a new field of international nephrology in recent years and plays an important role in the progression of chronic renal disease. CD137 was originally described as a surface molecule present on activated T and NK cells and detected on hypoxic endothelial cells and inflamed blood vessels, but its function on lymphatic endothelial cells remains unclear. We investigated the relationships among CD137, lymphangiogenesis and macrophages, which are involved in interstitial fibrosis. Similar to other chronic inflammatory diseases, we found lymphangiogenesis and expression of CD137 in the renal tissue of patients with IgA nephropathy. CD137-positive lymphatic vessels were involved in the development process of IgA nephropathy and positively correlated with serum creatinine, serum urea nitrogen, serum uric acid, and urinary 24 h total protein. The expression of these indicators was negatively correlated with eGFR, plasma albumin, and HB. In mouse models of UUO, we verified that CD137 expression was significantly elevated during lymphangiogenesis and that its ligand CD137L was released by macrophages after VEGF-C stimulation in the kidney. In vitro, recombinant CD137L significantly enhanced LEC proliferation, migration and tube formation, and these effects were inhibited by CD137 siRNA. Mechanistically, the CD137L interaction with CD137 induced the transition from LC3-I to LC3-II and the expression of Atg5, Atg7, Atg12 and p62 proteins by activating the PI3K/AKT/mTOR pathway to promote autophagy. Knockdown of Atg5 and Atg7 blocked CD137L-induced autophagy. Thus, we propose that CD137L secretion by macrophages interacts with CD137 on lymphatic endothelial cells to prompt lymphangiogenesis in the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the CD137-CD137L pathway is a novel therapeutic approach for obstructive nephropathy.

Cellular senescence of renal tubular epithelial cells in renal fibrosis

“…Klotho is highly expressed in normal kidneys, especially in the distal tubules, but oxidative stress, inflammation, angiotensin II, aldosterone and proteinuria, which are present during organ and organism aging and various CKD pathologies, can reduce Klotho expression (107). Klotho is a pleiotropic protein that downregulates a variety of cytokines and growth factors, such as IGF-1, Wnt/b-catenin and TGF-b1, and plays a variety of biological functions such as regulating cellular senescence, inhibiting apoptosis, inflammation, oxidative stress and regulating calcium and phosphorus metabolism (12, 108, 109), which plays a critical role in delaying renal aging, protecting the kidney from acute and chronic injury, promoting restoration of renal function and delaying the progression of RF and CKD (85,86,110). Therefore, it is possible to interfere with renal senescence by upregulating Klotho expression to inhibit RF and delay CKD progression.…”

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

“…[76,77] In chronic kidney fibrosis, kidney cell damage induces an inflammatory response that recruits inflammatory cells and activates resident fibroblasts and myofibroblasts. [78,79] Macrophages within the kidney secrete VEGF-C/D to promote lymphangiogenesis and sustain fibrosis, [80] and neutrophils stimulate LEC proliferation and lymphatic growth by releasing VEGF-C/D and increasing the bioavailability of ECM-bound VEGF-A. [81] In cardiac fibrosis that arises from acute myocardial injury, initial inflammatory responses, which include an influx of immune cells (e.g., macrophages, neutrophils) and increased expression of inflammatory cytokines, stimulate cardiac fibroblast activation.…”

“…[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).…”

Lymphangiogenesis and Lymphatic Barrier Dysfunction in Renal Fibrosis

“…In addition to VEGF, there are many additional factors released by macrophages at play. Binding of CD137 expressed on hypoxic LECs and CD137 ligand secreted by macrophages promotes growth of LVs in unilateral ureteral obstruction (UUO) mice [57]. Moreover, the close relationship between macrophages and LECs also contributes to lymphangiogenesis.…”