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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.

SUBMITTER: Zoccali C

PROVIDER: S-EPMC8713155 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDiabetic kidney disease (DKD) is the most common cause of the end-stage renal disease (ESRD). Regardless of intensive treatments with hyperglycemic control, blood pressure control, and the use of renin-angiotensin system blockades, the prevalence of DKD remains high. Recent studies suggest that the spectrum of DKD has been changed and many progresses have been made to develop new treatments for DKD. Therefore, it is time to perform a systemic review on the new developments in the field of DKD.SummaryAlthough the classic clinical presentation of DKD is characterized by a slow progression from microalbuminuria to macroalbuminuria and by a hyperfiltration at the early stage and progressive decline of renal function at the late stage, recent epidemiological studies suggest that DKD patients have a variety of clinical presentations and progression rates to ESRD. Some DKD patients have a decline in renal function without albuminuria but display prominent vascular and interstitial fibrosis on renal histology. DKD patients are more susceptible to acute kidney injury, which might contribute to the interstitial fibrosis. A large portion of type 2 diabetic patients with albuminuria could have overlapping nondiabetic glomerular disease, and therefore, kidney biopsy is required for differential diagnosis for these patients. Only a small portion of DKD patients eventually progress to end-stage renal failure. However, we do not have sensitive and specific biomarkers to identify these high-risk patients. Genetic factors that have a strong association with DKD progression have not been identified yet. A combination of circulating tumor necrosis factor receptor (TNFR)1, TNFR2, and kidney injury molecular 1 provides predictive value for DKD progression. Artificial intelligence could enhance the predictive values for DKD progression by combining the clinical parameters and biological markers. Sodium-glucose co-transporter-2 inhibitors should be added to the new standard care of DKD patients. Several promising new drugs are in clinical trials.Key messagesOver last years, our understanding of DKD has been much improved and new treatments to halt the progression of DKD are coming. However, better diagnostic tools, predictive markers, and treatment options are still urgently needed to help us to better manage these patients with this detrimental disease.

Project description:Neurological disorders are prevalent in patients with chronic kidney disease (CKD). Vascular factors and uremic toxins are involved with cognitive impairment in CKD. In addition, vascular dementia-induced alterations in the structure and function of the hippocampus can lead to deficits in hippocampal synaptic plasticity and cognitive function. However, regardless of this clinical evidence, the pathophysiology of cognitive impairment in patients with CKD is not fully understood. We used male Sprague Dawley rats and performed 5/6 nephrectomy to observe the changes in behavior, field excitatory postsynaptic potential, and immunostaining of the hippocampus following CKD progression. We measured the hippocampus volume on magnetic resonance imaging scans in the controls (n = 34) and end-stage renal disease (ESRD) hemodialysis patients (n = 42). In four cognition-related behavior assays, including novel object recognition, Y-maze, Barnes maze, and classical contextual fear conditioning, we identified deficits in spatial working memory, learning and memory, and contextual memory, as well as the ability to distinguish familiar and new objects, in the rats with CKD. Immunohistochemical staining of Na+/H+ exchanger1 was increased in the hippocampus of the CKD rat models. We performed double immunofluorescent staining for aquaporin-4 and glial fibrillary acidic protein and then verified the high coexpression in the hippocampus of the CKD rat model. Furthermore, results from recoding of the field excitatory postsynaptic potential (fEPSP) in the hippocampus showed the reduced amplitude and slope of fEPSP in the CKD rats. ESRD patients with cognitive impairment showed a significant decrease in the hippocampus volume compared with ESRD patients without cognitive impairment or the controls. Our findings suggest that uremia resulting from decreased kidney function may cause the destruction of the blood-brain barrier and hippocampus-related cognitive impairment in CKD.

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

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