Gradual replacement of functioning kidney tissue by cysts characterizes polycystic kidney disease (PKD). Cysts occur through two processes: (1) Epithelial cell proliferation, mediated by ERK, mTOR, and AMPK; and (2) Fluid secretion produced through CFTR activity. Our understanding of these disorders has grown dramatically in the past 2 decades through the use of genetically-altered mouse models. While some existing drugs slow cytogenesis and progressive kidney dysfunction in mice, clinical trials of these agents have not yet produced the treatment we need for these conditions.
Enter steviol, a major metabolite of stevioside. Sound familiar? This substance is 300 times sweeter than sucrose and marketed as a sweetener. In addition to tickling our sweet-tooths without caloric penalty, stevioside and steviol:
- Promote natriuresis and diuresis
- Have antiinflammatory effects
- Block renal organic ion transporters
- Induce insulin secretion
- Reduce chloride secretion in the gut and other organs via CFTR
Steviol retards renal cyst growth through reduction of CFTR expression and inhibition of epithelial cell proliferation in a mouse model of polycystic kidney disease
Varanuj Chatsudthipong, Chaowalit Yuajit, Chatchai Muanprasat, Suticha Kittayaruksakul, Sorin V. Fedeles, Anna-Rachel Gallagher, Stefan Somlo
Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand, Department of Internal Medicine, Genetic, Yale University School of Medicine, New Haven, CT
Experiments were performed in a mouse model of autosomal dominant or adult-onset PKD via knock-out of PKD1. On day 10 of life, mice received parenteral sterol for 14 days and then underwent euthanasia. The results at the whole-organ level are pretty impressive:
Further studies showed that sterol both reduced cellular proliferation and cyst expansion via CFTR. Steviol activates AMPK, even higher than its activity in wild-type mice. This then blocks activity of CFTR and mTOR, preventing both pathways that lead to cytogenesis in this disorder.
Does this mean PKD patients should start using stevia-based products? Well, it probably won't provide a benefit. These pups got 200 mg/kg of steviol. When stevia sold at your local food store gets metabolized, only about 1/3 becomes steviol. So 600 mg stevia produces 200 mg steviol...and adult humans weigh 50 or more kg. That's a lot of artificial sweetener, and it can have toxicity at these doses. We also do not know if the same dose per body weight would be used as in the mouse.
In other words, this compound shows promise as a therapeutic agent, although we need a lot more study to translate this paper to people. Given recent disappointments in clinical trials for PKD, steviol provides another ray of hope on the horizon.
This paper is now available as an article in press, unfortunately behind a paywall, here.