Autophagy in Immune-Related Renal Disease

Abstract

Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a "double-edged sword"-exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.

Figure 1

Immune-related renal disease. Aberrant immunity, such as autoimmune diseases, is a systemic disease. These immune disruptions, such as autoantibody production, immune complex formation, and disposition, can cause damage to any organ of our body, such as the heart, the lung, and the joints. However, the kidneys are susceptible to these immune-mediated damages, which results from its unique hemodynamic characteristics, kidney-specific DAMPs, and crystal formation in the tubule system. Besides, the renal resident cells, including podocytes, glomerular capillary epithelial cells, tubule epithelial cells, and mesangial, are also found to be susceptible to immune-mediated injuries.

Figure 2

Classic autophagy pathway. There are three major types of classic autophagy process in mammalians: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy includes four major steps: induction, elongation, and maturation of autophagosome and fusion with lysosome. Several protein complexes are involved in this process.

Figure 3

Autophagy in renal resident cells. The figure summarizes current studies of autophagy in renal resident cells, including podocytes, glomerular capillary epithelial cells, mesangial cells, and tubule epithelial cells. Upregulation or downregulation of autophagy activity through gene expression modulation or under certain stimulation can influence the survival of these cells and the overall function of the kidney. Taken together, autophagy plays a protective role in the physiology and pathophysiology of the kidney.

Figure 4

Autophagy dysfunction in lupus nephritis. Macrophagy eliminates neutrophil extracellular trap (NET) through autophagy. Autophagy deficiency in macrophagy leads to DNA exposure of NET, which activates adaptive immunity and produces anti-dsDNA antibodies. Autophagy dysfunction in podocytes fails to clear the autoantibodies, which subsequently binds to DNA fractions of NETs, forming immune complexes. These immune complexes will damage kidney and cause nephritis in lupus.