One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation.

Observational studies have associated the increase in fibroblast growth factor (FGF) 23 levels, the main regulator of phosphate levels, with the onset of diabetes. These studies open the debate on the plausible existence of undescribed diabetogenic mechanisms derived from chronic supraphysiological levels of FGF23, a prevalent condition in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. These maladaptive and diabetogenic responses to FGF23 may occur at different levels, including a direct effect on the pancreatic ß cells, and an indirect effect derived from the stimulation of the synthesis of pro-inflammatory factors. Both mechanisms could be mediated by the binding of FGF23 to noncanonical receptor complexes with the subsequent overactivation of signaling pathways that leads to harmful effects. The canonical binding of FGF23 to the receptor complex formed by the receptor FGFR1c and the coreceptor αKlotho activates Ras/MAPK/ERK signaling. However, supraphysiological concentrations of FGF23 favor non-αKlotho-dependent binding of this molecule to other FGFRs, which could generate an undesired overactivation of the PLCγ/CN/NFAT pathway, as observed in cardiomyocytes and hepatocytes. Moreover, the decrease in αKlotho expression may constitute a contributing factor to the appearance of these effects by promoting the nonspecific activation of the PLCγ/CN/NFAT to the detriment of the αKlotho-dependent Ras/MAPK/ERK pathway. The description of these mechanisms would allow the development of new therapeutic targets susceptible to be modified by dietary changes or by pharmacological intervention.