Increase in apoptosis following down-regulation of tubular β-catenin signaling in chronic kidney disease

A healthy kidney, only as big as the size of a fist, works to get rid of waste and excess water from the blood in the form of urine. When the kidneys are functioning properly, they maintain chemical balances, help regulate blood pressure, and produce hormones that act throughout the body. However, nearly 10% of the world’s population suffers from kidney disease, where their kidneys are not able to function and filter blood properly. When this happens, there is a build-up of waste and excess nutrients, which can cause numerous health concerns such as diabetes, high blood pressure, and cardiovascular disease.

Glomerular filtration rate (GFR) is used to determine the ability of kidneys to filter blood. Although kidneys typically lose function as an individual ages, they can still work effectively even at a lower GFR. In fact, most people with chronic kidney disease do not notice any symptoms until they have lost nearly 75% function. Once a patient’s GFR falls under 30%, they are deemed to be in the early stages of renal failure, and at 15%, severe treatment such as external, artificial filtration (known as dialysis) or kidney transplant for end-stage renal failure is necessary.

Doctors and scientists investigate kidney function by testing albumin and creatinine levels in urine. Albumin is a protein that is barely detectable in the urine of a healthy individual but found in excess when kidneys no longer filter at an adequate rate, which leads ultimately to increased proteinuria. Creatinine is a natural waste product constantly produced by the body. Contrary to albumin, it builds-up to surplus levels in the blood of patients with kidney disease when not filtered out properly. Increased albumin-to-creatinine ratio in urine is an indication that kidney function is affected.

Researchers are currently looking at the involvement of different signaling pathways in the abnormal protein build-up and the toxic mechanisms observed in patients with kidney disease. Specifically, the Wnt/β-catenin signaling pathway was shown to play a key role in that process. Dr. Wong and colleagues from the Division of Nephrology at the University of Hong Kong examined the Wnt/β-catenin pathway and the different effects it had on kidney epithelial cells and other biological proteins. By inducing protein overload in mouse cells, the researchers saw an initial knockout of the Wnt/β-catenin signaling pathway. Dkk3 is a member of the Dickkopf protein family and it provides feedback control of the Wnt/β-catenin signaling pathway. This protein was specifically found to have a mediating effect on protein overload. Wnt/β-catenin signaling is known to produce continuous cell growth, but when down-regulated by protein overexpression, the research team demonstrated kidney injury via apoptotic mechanisms. Ultimately, immunohistochemical (IHC) staining of mouse kidney tissues showed that downregulation of Wnt/β-catenin signaling, through the control of Dkk-3, leads to high protein build-up in urine, as well as renal cell death. Using Enzo’s HIGHDEF® red IHC chromogen (AP), the authors of this study highlighted the expression of aquaporin-1, an integral channel protein that transfers water and small solutes across the membrane, alongside β-catenin. Due to the interaction between aquaporin-1 and -catenin in the kidney, localization of aquaporin-1 served as a marker for the presence of β-catenin at different endpoints in the signaling pathway. The absence of this molecule was indicative of high protein concentrations and consequently, kidney disease. Future work to improve and maintain this pathway could be helpful in finding cures for the effects of chronic kidney failure.

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