The role of innate immunity in pathogenesis of diabetic nephropathy

Abstract

Diabetic nephropathy is one of the most important causes of end-stage renal disease around the world, as a result of 1) the growing prevalence of Type 2 diabetes mellitus, which in turn reflects the increasing prevalence of overweight and obesity, as well as aging of the world's population; 2) increased survival of diabetic patients thanks to numerous therapeutic advances. The mechanisms that lead to the development of diabetic nephropathy remain unclear. Intracapillary hypertension and/or glomerular hypertrophy can initiate and/or aggravate the process, whereas several nonhemodynamic mechanisms such as non-enzymatic glycation of proteins, podocyte injury and inflammation likely play an equally important role. In recent years, activation of innate immunity has been pointed out as a potentially important event in the pathogenesis of diabetic and nondiabetic glomerular and tubular injury. Prolonged exposure to high glucose concentrations is a known stimulus for the assembly of inflammasomes in cultured cells, whereas recent in vivo evidence suggests that activation of innate immunity can indeed exert a relevant pathogenic role in diabetic nephropathy. In the present study, we propose to investigate the role of innate immunity in the model of streptozotocin induced diabetic nephropathy. We intend to conduct a longitudinal long-term study, analyzing the activation of innate immunity in the incipient stages of the process, when proteinuria is still low, and in later stages, when the histological manifestations of glomerular injury have become evident. In this manner, we expect to contribute to clarify the pathogenesis of diabetic nephropathy, and to characterize potential targets for the treatment of this condition. (AU)