Chronic kidney disease (CKD) is a major public health issue, affecting over 10 percent of the global population, frequently occurring as a result of other disorders such as hypertension, diabetes, obesity, or metabolic syndrome. An early sign of CKD is the increased level of liver protein albumin in the urine, also known as albuminuria. Shown to damage the glomerulus, the kidney’s filtering system, albuminuria is also a proven risk factor in end-stage renal failure, with diabetic kidney disease taking the top spot as the leading cause of kidney failure worldwide. Therefore, strategies to prevent albuminuria have important connotations, particularly in the first stages of CKD. Now, a study from researchers at the University of Bristol discovers an important cell signaling pathway in the kidney holding great potential to treat CKD. The team states they have linked a signaling molecule present in high levels in the brain called Neuropeptide Y (Npy) to raised levels of albuminuria and damage to the glomerulus. The opensource study is published in the Proceedings of the National Academy of Sciences (PNAS).
Previous studies show albuminuria is an independent risk factor for kidney failure, cardiovascular morbidity, as well as premature death, with the identification of signaling pathways capable of modulating albuminuria highly desirable. So far, research has concentrated on podocytes, the lining of the glomerulus on the urinary side of the filtration barrier, with past studies confirming damage to this epithelial lining as a key driver of albuminuria and glomerular disease in numerous pathologies. However, the molecular pathways involved in podocyte injury are unclear. The current study performs transcriptomes for insulin-sensitive and insulin-resistant podocytes in diabetic mouse kidneys to identify Npy as the most highly downregulated transcript.
The current study investigates two groups of diabetic mice, one group with the ability to produce Npy, and the other group unable to produce the peptide of interest. Results show mice lacking Npy were protected from both diabetic and non-diabetic kidney disease. Data findings suggest the reduction of Npy in the glomerulus is a protective mechanism to reduce the amounts of damaging Npy channeled to the kidney, as opposed to causing a problem.
The lab states in both human and mouse podocytes, Npy was found to signal via the NPY receptor 2, modulating PI3K, MAPK, and NFAT signaling causing nephrotoxicity if prolonged. They go on to add these results demonstrate the effects of Npy at the filtration barrier, proffering NPY receptor 2 signaling as a therapeutic intervention for albuminuric-based kidney disease. The mice with kidney disease were then given a drug to block the NPY Receptor 2 which successfully protected against both albuminuria and kidney disease.
The team surmises the pharmaceutical ablation of a brain signaling pathway in a diabetes mouse model could possibly prevent the development of albuminuria and kidney disease. For the future, the researchers state the discovery of Npy’s detrimental potential in the kidney and ways to block it could play a vital role in developing new treatments for CKD.
Source: University of Bristol
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