Glomerulonephritis (GN) generally arises as a result of a series of events, which depending on their severity can lead to kidney failure and death. Typically, some insult causes the formation of large quantities of insoluble antigen — antibody immune complexes (ICs) in the blood, which are carried to the kidney for clearance (Figure 1A). Besides the obvious inflammation caused by ICs and responding leukocytes, GN is characterized by elevation of local blood pressure, accumulation of extracellular matrix (ECM), and deterioration of ionic balance, all of which contribute to nephron failure. Several recent studies have examined the complex array of interactions among cytokines, chemokines and their receptors, and how they are involved in GN at the level of the individual juxtaglomerular apparatus.
In addition to the overabundance of ICs, leukocytes responding and inciting inflammation overwhelm, and nearly occlude, glomerular capillaries resulting in obstructions that elevate glomerular blood pressure.1,2 One of the factors luring macrophages to the site is IFN-gamma. IFN-gamma-induced upregulation of ICAM-1 and VCAM-1 on capillary and tubule surfaces contributes to selectin-bearing macrophage accumulation and infiltration.3,4 Proinflammatory stimuli, such as IL-1 and TNF-alpha, also increase endothelial cell E- and P-selectin expression, further contributing to leukocyte accumulation.4 IFN-gamma enhanced MCP-1 expression and secretion from tubule cells and macrophages augments CCR2+ macrophage recruitment.3,5 Moreover, increases in both soluble and membrane-anchored Fractalkine expression by glomerular capillary epithelial cells causes the recruitment and adhesion of CX3CR1+ macrophages. While Fractalkine upregulation may be induced by other cytokines and chemokines, it may be a compounding result of the increase in local hypertension caused by blood flow obstructing ICs and leukocytes.6 Slowed blood flow and, hence, elevated blood pressure in the glomerulus lead to microaneurysms, which eventually rupture and destroy its structure. Nearby tissues are also compromised as a result of hypoperfusion and ischemia caused by hypertension-induced vessel damage (Figure 1B).1,2
Dysregulation of the ECM further damages the juxtaglomerular apparatus by perturbing its structure. TGF-beta is one of the major factors regulating ECM formation. MCP-1, via its receptor CCR2 expressed on glomerular cells, stimulates upregulation of TGF-beta causing aberrantly high levels of ECM deposition, particularly type IV collagen.5 ECM turnover is regulated by MMP and ADAM proteolytic activity. Protease inhibition experiments suggest that depressed MMP activity, particularly MMP-2, leads to decreased ECM degradation and excessive ECM accumulation characteristic of GN.7 Via impaired regulation of both ECM deposition and degradation, ECM accumulation imposes structural alterations on the juxtaglomerular apparatus which leads to fibrosis and sclerosis (Figure 1B).5,7
Regulation of ionic balance in both glomerular blood and tubule filtrate is critical for maintaining proper nephron, and therefore, kidney function. Glomerular production of IP-10 and MIG is elevated in GN.8 MIG binds its receptor, CXCR3, expressed on proximal tubule cells eliciting Ca2+ influx. Ca2+ causes upregulation of the transcription factor, EGR-1, subsequently suppressing superoxide dismutase (SOD) expression and leading to an increase of superoxide (SO) radicals. These reactive oxygen species then inhibit the function of the Na+/K+ ATPase resulting in depressed Na+ resorption and increased Na+ excretion, often associated with many types of GN and kidney failure (Figure 1C).9