Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease: translational opportunities and challenges

Abstract

Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.

Keywords: CKD; cardiovascular; dialysis; hypertension; renin–angiotensin system.

Figure 1:

The NPY and the gut–brain axis. The graph shows the YR subtypes that mediate the effects of NPY in the CNS and at the different levels of the gut–brain axis. ↑: increase; ↓: decrease.

Figure 2:

Selectivity within the NPY family. (A) The three endogenous ligands—NPY, PYY and PP—exhibit varying degrees of affinity and specificity for four human YRs. The ligand potency at the respective receptor is reflected by the size of the sphere above. NPY and PYY bind with relatively high affinity to Y1R, Y2R and Y5R. In contrast, PP binds predominantly to Y4R and with lower affinity to Y5R. (B) Phylogeny of the human YRs resulting in three receptor subfamilies and defined preference towards a specific receptor subtype.

Figure 3:

NPY receptors. Y1R, Y2R, Y4R and Y5R are the four active receptors in mammals. yR6 is functionally inactive and YR7 and YR8 got lost in the lineage leading to mammals.

Figure 4:

The figures upon which the graph is based were derived from data reported in the Human Protein Atlas. Consensus normalized expression (NX) levels of NPY for the CNS created by combining the data from the three transcriptomics datasets using internal normalization criteria (see also main text).