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Investigating the effects of soy phytoestrogens on Nephrin and Akt podocyte survival signaling pathway

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Title: Investigating the effects of soy phytoestrogens on Nephrin and Akt podocyte survival signaling pathway
Author: Mahesaniya, Afreeda
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Jones, Nina
Abstract: Chronic kidney disease (CKD) is a debilitating illness which is increasing in frequency in the Canadian population as a consequence of the diabetes epidemic. Physicians and patients are becoming increasingly interested in using lifestyle modifications to supplement treatment and improve clinical outcomes. Anecdotal evidence suggests that a soy-based diet, which consists of phytoestrogens – daidzein and genistein, can decrease proteinuria in CKD patients, although the molecular mechanisms behind this phenomenon remain unknown. The ability of the kidneys to properly filter blood is vitally dependent on specialized, terminally differentiated cells known as podocytes, loss of which results in altered filtration selectivity. Podocytes extend foot processes, which are bridged by the slit diaphragm (SD), a specialized intercellular junction. Perturbations in nephrin, a major SD protein, compromise podocyte survival and ultimately filtration function. Nephrin elicits signaling via phosphorylation of tyrosine residues on its cytoplasmic tail, leading to recruitment and activation of proteins including the survival signaling protein Akt. We have now shown that nephrin/Akt signaling is enhanced in mice following feeding of a soy-based diet. Intriguingly, this observation is more pronounced in female compared to male mice, implicating that sex-specific differences, such as those imposed by the estrogen receptor (ER), may play an important role in this response. Accordingly, soy supplementation induces activation of Akt, which is a known target of the activated ER and a key regulator of podocyte survival. Using cultured podocytes, we further demonstrate that treatment with daidzein promotes podocyte protection following high glucose exposure. Altogether, this work provides mechanistic insight to support the renoprotective effects of soy and its sex-specific effects on kidney function, in addition to identifying an optimal dosage and duration of soy supplementation in mice which is clinically applicable.
Date: 2017-09
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