Hyperphosphatemia associated with chronic kidney disease is one of the factors that can promote vascular calcification, and intestinal P(i) absorption is one of the pharmacological targets that prevents it. The type II Na-P(i) cotransporter NaPi-2b is the major transporter that mediates P(i) reabsorption in the intestine. The potential role and regulation of other Na-P(i) transporters remain unknown. We have identified expression of the type III Na-P(i) cotransporter PiT-1 in the apical membrane of enterocytes. Na-P(i) transport activity and NaPi-2b and PiT-1 proteins are mostly expressed in the duodenum and jejunum of rat small intestine; their expression is negligible in the ileum. In response to a chronic low-P(i) diet, there is an adaptive response restricted to the jejunum, with increased brush border membrane (BBM) Na-P(i) transport activity and NaPi-2b, but not PiT-1, protein and mRNA abundance. However, in rats acutely switched from a low- to a high-P(i) diet, there is an increase in BBM Na-P(i) transport activity in the duodenum that is associated with an increase in BBM NaPi-2b protein abundance. Acute adaptive upregulation is restricted to the duodenum and induces an increase in serum P(i) that produces a transient postprandial hyperphosphatemia. Our study, therefore, indicates that Na-P(i) transport activity and NaPi-2b protein expression are differentially regulated in the duodenum vs. the jejunum and that postprandial upregulation of NaPi-2b could be a potential target for treatment of hyperphosphatemia.

Phosphate is absorbed in the small intestine by at least two distinct mechanisms: paracellular phosphate transport which is dependent on passive diffusion and active transport which occurs through the sodium-dependent phosphate co-transporters. Despite evidence emerging for other ions, regulation of the phosphate specific paracellular pathways remains largely unexplored. In contrast, there is a growing body of evidence that active transport through the sodium-dependent phosphate co-transporter Npt2b is highly regulated by a diverse set of hormones and dietary conditions. Furthermore, conditional knockout of Npt2b suggests that it plays an important role in maintenance of phosphate homeostasis by coordinating intestinal phosphate absorption with renal phosphate reabsorption. The knockout mouse also suggests that Npt2b is responsible for the majority of sodium-dependent phosphate uptake. The type III sodium-dependent phosphate transporters, Pit1 and Pit2 contribute a minor role in total phosphate uptake. Despite co-expression along the apical membrane, differential responses of Pit1 and Npt2b regulation to chronic versus dietary changes illustrates another layer of phosphate transport control. Finally, a major problem in chronic kidney disease (CKD) patients is management of hyperphosphatemia. The present evidence suggests that targeting key regulatory transporters of intestinal phosphate transport may provide novel therapeutic approaches for CKD patients.

Genome-wide association studies (GWAS) have proven a fundamental tool to identify common variants associated to complex traits, thus contributing to unveil the genetic components of human disease. Besides, the advent of GWAS contributed to expose unexpected findings that urged to redefine the framework of population genetics. First, loci identified by GWAS had small effect sizes and could only explain a fraction of the predicted heritability of the traits under study. Second, the majority of GWAS hits mapped within non-coding regions (such as intergenic or intronic regions) where new functional RNA species (such as lncRNAs or circRNAs) have started to emerge. Bigger cohorts, meta-analysis and technical improvements in genotyping allowed identification of an increased number of genetic variants associated to coronary artery disease (CAD) and cardiometabolic traits. The challenge remains to infer causal mechanisms by which these variants influence cardiovascular disease development. A tendency to assign potential causal variants preferentially to coding genes close to lead variants contributed to disregard the role of non-coding elements. In recent years, in parallel to an increased knowledge of the non-coding genome, new studies started to characterize disease-associated variants located within non-coding RNA regions. The upcoming of databases integrating single-nucleotide polymorphisms (SNPs) and non-coding RNAs together with novel technologies will hopefully facilitate the discovery of causal non-coding variants associated to disease. This review attempts to summarize the current knowledge of genetic variation within non-coding regions with a focus on long non-coding RNAs that have widespread impact in cardiometabolic diseases.