Endothelial cells: potential novel regulators of renal inflammation

Abstract

Substantial evidence has supported the role of endothelial cell (EC) activation and dysfunction in the development of hypertension, chronic kidney disease (CKD), and lupus nephritis (LN). In both humans and experimental models of hypertension, CKD, and LN, ECs become activated and release potent mediators of inflammation including cytokines, chemokines, and reactive oxygen species that cause EC dysfunction, tissue damage, and fibrosis. Factors that activate the endothelium include inflammatory cytokines, mechanical stretch, and pathological shear stress. These signals can activate the endothelium to promote upregulation of adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which promote leukocyte adhesion and migration to the activated endothelium. More importantly, it is now recognized that some of these signals may in turn promote endothelial antigen presentation through major histocompatibility complex II. In this review, we will consider in-depth mechanisms of endothelial activation and the novel mechanism of endothelial antigen presentation. Moreover, we will discuss these proinflammatory events in renal pathologies and consider possible new therapeutic approaches to limit the untoward effects of endothelial inflammation in hypertension, CKD, and LN.

Keywords: antigen presentation; endothelial cells; inflammation; kidney injury; renal.

Graphical abstract

Figure 1.

Immunological receptors of endothelial cells. Endothelial cells express number pattern recognition receptors including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs) on the plasma membrane, on the endosomal membrane, and in the cytoplasm. Moreover, endothelial cells express cytokine receptors including interferon receptors (IFNARs) and tumor necrosis factor (TNF) receptor 1 (TNFR1). These receptors act as a first line of immunological defense for endothelial cells and subsequent intracellular signaling leads to NF-κB and activator protein (AP)-1 transcription orchestrating endothelial activation and inflammation. Pathological activation of these receptors can lead to endothelial dysfunction, recruitment of immune cells, and the development of end-organ damage in both cardiovascular and renal disease states including hypertension, acute kidney injury, and lupus nephritis.

Figure 2.

Role of physiological stress on activation on endothelial cells. Mechanical mechanisms including oscillatory shear stress and uniaxial hypertensive stretch activate the endothelium to propagate a proinflammatory response. Under normal physiological conditions including laminar shear stress, the endothelium produces large amounts of nitric oxide (NO) and has low expression of adhesion molecules [intracellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1); left]. During pathological conditions including chronic kidney disease, hypertension, and lupus nephritis, the endothelium becomes activated and upregulates adhesion molecules (ICAM-1 and VCAM-1) and produces copious amount of reactive oxygen species (H₂O₂ and ${\text{O}}_2^{-}$) and proinflammatory cytokines. This activated endothelial state promotes leukocyte activation, migration, and adhesion promoting end-organ inflammation and damage in hypertension, chronic kidney disease, and systemic lupus erythematosus. MHC, major histocompatibility complex.

Figure 3.

Endothelial cells as novel antigen-presenting cells. Multiple inflammatory stimulation by interferon (IFN)-γ or tumor necrosis factor (TNF)-α promotes endothelial inflammation. These stimuli promote upregulation of intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and major histocompatibility complex (MHC) II. Upregulation of MHC II has been demonstrated to activate both CD4⁺ and CD8⁺ T cells along with adequate costimulation through molecules such as CD80, CD86, and inducible costimulator ligand. This critical signaling pathway could play a novel and critical role in the development of chronic kidney disease, hypertension, and various autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis. IFNR, IFN receptor; PDL, program death-1 ligand; TCR, T cell receptor.

Figure 4.

Endothelial inflammation and activation in renal disease states. Endothelial activation, dysfunction, and inflammation comprise a complex orchestration of numerous cell types, adhesion molecules, and cytokines/chemokines that play a critical role in the development of numerous renal pathological disease states. In acute kidney injury (AKI; top left), the endothelium secretes chemokine (C-X3-C motif) ligand 1 (CX₃CL1), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-X-C motif) ligand 1 (CXCL1) to promote macrophage, monocyte, and neutrophil homing. Moreover, upregulation of adhesion molecules [intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and P-selectin] promotes rolling, adhesion, and diapedesis of immune cells to the subendothelial layer to promote vascular and organ inflammation. In lupus nephritis (top right), there is an increase in autoantibody production that can lead to the binding of endothelial cells (ECs). The endothelium secretes proinflammatory cytokines [interleukin (IL)-6, IL-1β, and IL-18] and chemokines [monocyte chemoattractant protein-1 (MCP-1)] to promote immune cell activation and homing to the site of EC injury. Moreover, there is a decrease in nitric oxide (NO) bioavailability and increase in reactive oxygen species (ROS) production promoting a proinflammatory and prooxidant status at the environment of the endothelium. Immune cells, including monocytes and neutrophils, home to the subendothelial layer and promote tissue inflammation. Finally, there is an upregulation in membrane-bound adhesion molecules (ICAM-1) and soluble adhesion molecules (sICAM-1). In diabetic nephropathy (bottom left), the endothelium secretes copious amounts of tumor necrosis factor (TNF)-α, IL-6, IL-8, IL-18, and IL-1 to promote monocyte, macrophage, and neutrophil activation. Moreover, the endothelium produces ROS, upregulates adhesion molecules [ICAM-1, VCAM-1, and endothelial-leukocyte adhesion molecule-1 (ELAM-1], secretes key chemokines to promote adhesion and diapedesis of immune cells into the surrounding tissue. Finally, in coronavirus disease-2019 (COVID-19; bottom right), there is circulating severe acute respiratory virus-related coronavirus-2 (SARS-CoV-2) virus that binds to angiotensin-converting enzyme 2 (ACE2) receptors on the endothelium. This in turn upregulates ICAM-1, VCAM-1, and vascular adhesion protein (VAP-1) to promote immune cell adhesion. Macrophages, monocytes, and neutrophils transmigrate to the subendothelium and promote vasculitis and vascular dysfunction. Finally, as cells undergo cell death, endothelial Toll-like receptor activation promotes cytokine production and further inflammation in a feedforward mechanism.