RAGE Ligands and Kidneys
Expression of RAGE and its ligands is kept at a low level in a wide range of cell types, including endothelium, smooth muscle cells, mononuclear phagocytes, neurons, and cardiac myocytes [22]. However, when RAGE ligands are accumulated by pathological development of relevant diseases, it alters the structure of tissues as well as compromise protein function in them [23, 24]. Also, increased circulating RAGE ligands induce the expression of their receptor, RAGE; therefore, RAGE ligand signals are stimulated as the ligands increase [16]. In kidneys, accumulation of RAGE ligands is well studied to contribute to both diabetic and non-diabetic nephropathy (DN). Firstly, AGEs have been found primarily to be up-regulated in renal basement membranes in diabetic nephropathies and in some other renal diseases, including glomerulosclerosis and arteriosclerosis, which are not related to diabetes [25]. In diabetes, AGEs are highly accumulated by increasing mitochondrial production of reactive oxygen species, followed by high intracellular glucose levels [26]. Abnormally high concentrations of AGEs impair proximal tubular cells, which are responsible for regulation of AGE metabolism, resulting in damage to those cells and their function [27, 28]. Also, kidneys play key roles in the clearance of AGEs, such that the impaired structure of the kidneys by AGEs fails to degrade them [29]. In turn, more and more AGEs are accumulated as the kidney is damaged by the action of AGEs, and finally, it results in DN [27, 28, 30]. Recently, increasing evidence has shown that RAGE ligands other than AGEs, including HMGB1 and S-100 proteins, are also up-regulated in renal diseases. HMGB1 is a nuclear protein essential for regulating the physical interaction of DNA with certain transcription factors, such as p53 [29]; however, when it is released extracellularly, it is able to mediate inflammatory reactions and contribute to the pathogenesis of several diseases, including glomerulonephritis, lupus nephritis, and renal cell carcinoma (RCC) [31, 32]. In addition, cell proliferation, migration, and invasion as well as inflammation are also activated in RCC via ERK1/2 activation [32].
Interaction between RAGE and its ligands changes renal cellular processes, including inflammation, proliferation, and migration, and they are highly significant processes to keep the normal function of kidneys; therefore, dysregulation of RAGE or its ligand concentrations might give fatal effects, leading to the development and pathogenesis of renal diseases.