Sgk1 como mediador de los efectos deletéreos del receptor de mineralocorticoides

Resumen

The mineralocorticoid receptor (MR) plays a central role in mineral homeostasis, extracellular volume control and blood pressure regulation. However, MR is expressed in others tissues not directly related with these processes, where it can be activated by both mineralocorticoids and glucocorticoids. Inappropriate MR activation results in pro-fibrotic activity in the cardiovascular and renal systems, independently of effect on blood pressure. More recently, it has been described that MR overactivation leads to the development of obesity and metabolic syndrome. MR antagonists (MRAs) are used in clinical practice as cardiovascular protecting agents, independently of their antihypertensive activity. Moreover it has been shown that MRAs improve glucose tolerance and insulin resistance reducing plasma levels of pro-inflammatory cytokines and triglycerides in preclinical models. However, MRAs may produce several adverse effects, like hyperkalemia, sexual dysfunction and hipovolemia. For this reason it would be important, from a therapeutic point of view, to identify genes that simultaneously mediate several of the various negative effects of MR. In this context we studied SGK1, a transcriptional target of MR that increases tubular Na+ reabsortion and salt appetite. SGK1 has been involved in several fibrotic diseases and adipogenesis. This work investigates the role of SGK1 in MR-induced processes that lead to an increase in cardiovascular risk including hypertension, metabolic syndrome and renal injury. To that end we used a mouse model with systemic increase on SGK1 activity. This model represents a closer approximation to physiopathological settings, compared with overexpression models or knockout of the kinase gene. Our results indicate that increased SGK1 activity accelerates mineralocorticoid-induced kidney injury and identified new potential genes involved in the effect. In addiction, the data demonstrated that SGK1 alters glucose handling and energy metabolism, leading to the development of many of the disorders characteristics of metabolic syndrome, including hypertension. Finally, we validated two additional genes, CTGF and PTGD, as direct MR targets that are directly or indirectly involved in the development of cardiovascular disease.