RAGE and Renal Diseases

Diabetic nephropathy
DN is one of the diseases triggered by diabetes and finally leads to renal failure and elevation of arterial blood pressure [33]. Cellular mechanisms involved in the development and pathogenesis of DN include glomerular hypertrophy, production of oxidative stresses, fibrosis, and inflammation, followed by hyperglycemia. As mediators, renin, angiotensin, aldosterone, protein kinases, and NADPH are existing, and hyper-activation of them results in up-regulation of fibrotic and inflammatory factors, including TGF-β [33-36]. Also, hyperglycemia stimulates glycation and oxidation of macromolecules, which result in the formation of AGEs as endproducts [37]. Accumulated AGEs join in the up-regulation of inflammatory factors and oxidative stress and accelerate the pathogenesis of the disease [38].

Cardio-renal syndrome
Cardio-renal syndrome is a combined disorder having both heart and kidney dysfunction. The primary failed organ can be either the heart or kidney, and in both cases, the one that is diseased earlier impairs the other one, and finally, they negatively affect each other [37]. One of the suggested mechanisms making these two organs negatively interact with each other is mediated by AGEs [39]. Accumulation of AGEs is commonly observed in patients with both heart failure and renal disorders [40, 41]. With heart failure, increase of AGEs leads to inflammation, fibrosis, and delayed calcium uptake, which subsequently result in diastolic dysfunction. In addition, accumulation of AGEs in renal dysfunction is negatively affected by highly activated inflammation and fibrosis, and further damage of kidney structure impairs its own function of AGE clearance [39]. Symptoms of the disease might be enhanced by this vicious cycle, as well as with other multifactorial signaling pathways involved in the pathogenesis.

Autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease is one of the most highly prevalent inherited disorders and is characterized by the development of thousands of epithelial-lined, fluid-filled cysts in the kidney [42]. Cell proliferation, inflammation, and fibrosis are the major processes of the development and pathogenesis of the disease, and various factors, including chemokines and growth factors, are engaged in these signaling pathways [43-45]. Recently, several studies have reported that expression of HMGB1 and certain types of S-100 (S-100A8, 9) is increased around the cystic region and proposed them to be disease-stimulating agents [46-48]. So, inflammatory and growth factors secreted by cyst-lined epithelial cells and increased circulating AGEs finally result in compromised renal function at the end stage of the disease.

Renal cell carcinomas
RAGE and its ligands are reported to be abnormally expressed in various cancers, including breast, lung, kidney, thyroid, prostate, and oral cancers. S100 protein, one of the representative ligands of RAGE, which has at least over 20 subtypes, has been well reviewed to play major roles in tumor-related processes, including proliferation, apoptosis, metastasis, and invasion [10]. In renal cancer, S100A1 has been observed to be highly expressed in papillary RCC and oncocytoma, which are relatively common types of renal cancers, whereas it is absent in chromophobe RCC [49]. Likewise, a broad range of S100 proteins has been detected differently, depending on the subtype of renal carcinoma, which means that it should be a useful biomarker for discriminating the subtype of renal cancers if it is correctly examined [50]. In addition, HMGB1, another ligand of RAGE, has appeared to be up-regulated and interacts with its receptor for promoting cell proliferation, migration, and invasion via the ERK pathway in RCC [32]. From this evidence, RAGE and its multiple ligands are increasingly suggested as biomarkers and therapeutic targets for different types of renal carcinomas.