The Players: Cells Involved in Glomerular Disease

Abstract

Glomerular diseases are common and important. They can arise from systemic inflammatory or metabolic diseases that affect the kidney. Alternately, they are caused primarily by local glomerular abnormalities, including genetic diseases. Both intrinsic glomerular cells and leukocytes are critical to the healthy glomerulus and to glomerular dysregulation in disease. Mesangial cells, endothelial cells, podocytes, and parietal epithelial cells within the glomerulus all play unique and specialized roles. Although a specific disease often primarily affects a particular cell type, the close proximity, and interdependent functions and interactions between cells mean that even diseases affecting one cell type usually indirectly influence others. In addition to those cells intrinsic to the glomerulus, leukocytes patrol the glomerulus in health and mediate injury in disease. Distinct leukocyte types and subsets are present, with some being involved in different ways in an individual glomerular disease. Cells of the innate and adaptive immune systems are important, directing systemic immune and inflammatory responses, locally mediating injury, and potentially dampening inflammation and facilitating repair. The advent of new genetic and molecular techniques, and new disease models means that we better understand both the basic biology of the glomerulus and the pathogenesis of glomerular disease. This understanding should lead to better diagnostic techniques, biomarkers, and predictors of prognosis, disease severity, and relapse. With this knowledge comes the promise of better therapies in the future, directed toward halting pathways of injury and fibrosis, or interrupting the underlying pathophysiology of the individual diseases that lead to significant and progressive glomerular disease.

Cytosolic Sensors of Viral RNA Are Involved in the Production of Interleukin-6 via Toll-Like Receptor 3 Signaling in Human Glomerular Endothelial Cells

“…The TLR3/ IFN-β/MDA5/RIG-I/IL-6 axis may play a role in inflammatory reactions related to viral and ‘pseudoviral” infection in GECs, and IL-6 produced by such cells may induce immune and inflammatory reactions in other resident glomerular cells [11, 12]. Since GECs have been reported to interact with other intrinsic residual glomerular cells [1, 2, 11], initial regional neutrophil recruitment by GECs followed by TLR3 activation could trigger the development of GN, as is thought to occur in LN [5, 6, 8, 22]. Thus, identifying the specific mechanisms that underlie endothelial TLR3 signaling for the recruitment of circulating neutrophils via CXCL1, E-selectin, and IL-6 expression is desirable for the development of therapeutic strategies for GN [8, 22].…”

“…In addition to contributing to the formation of the blood vessels in glomeruli, which act as a glomerular filtration barrier, glomerular endothelial cells (GECs) have been shown to produce various functional molecules that regulate aspects of glomerular function, including blood coagulation, inflammation, and homeostasis [1, 2]. Dysregulated endosomal Toll-like receptor (TLR) signaling has been reported to result in sustained activation of the type I interferon (IFN) system, which may lead to the development of autoimmune diseases such as systemic lupus erythematosus [3].…”

Toll-Like Receptor 3 Signaling Contributes to Regional Neutrophil Recruitment in Cultured Human Glomerular Endothelial Cells

“…Since GECs have also been reported to interact with intrinsic MCs, glomerular basement membrane and podocytes in the glomerulus [1, 2, 23], initial GEC injury followed by regional neutrophil recruitment could trigger the development of GN. Furthermore, the activation of TLR3 and downstream immune responses can be induced by both infectious pathogens and non-infectious stimuli such as endogenous ligands [13, 15], thus identifying that the specific mechanisms that underlie TLR3 signaling in GECs is desirable for developing therapeutic strategies for GN.…”

“…Injury to any of these intrinsic cell types can therefore lead to the development of glomerulonephritis (GN) [1, 2]. It has also been reported that neutrophils, another circulating player, play a pivotal role in the initiation of GN [3].…”

Measuring and interpreting platelet-leukocyte aggregates

“…While many renal pathologies are caused by leukocyte-mediated tissue injury (103,104), clinical and experimental data suggest a central role for platelets in a number of chronic and acute kidney disorders. In experimental mouse models and patients with different types of glomerulonephritis platelets accumulate in the kidneys and/or platelet-derived factors are systemically elevated (21,22,105–108).…”