Novel Regulators of Diet-Mediated Nephrocyte Dysfunction in Drosophila
Diabetic nephropathy is a complex disease with effects on the renal system and, appreciated more recently, the glomerular system including the podocyte. Podocyte foot effacement and substantial molecular changes occur in T2DM patients, leading to progressive loss of filtration and cell shedding that initiate early in disease progression. These defects are due to disruption of the glomerular basement membrane and/or disruption of the slit diaphragm, filtering structures associated with the podocytes. Recently we have found evidence for a pathway in flies that links elevated dietary sugar to reduced expression of Sns, a fly ortholog of the slit diaphragm protein Nephrin. We have partly validated our results in mammalian models. Loss of Sns—analogous to loss of Nephrin—led to dysfunction of the nephrocyte, a group of cells analogous to our own glomerulus. We have established a 'core pathway' that links dietary sugar to reduction of Sns and Nephrin. Here we expand our efforts, exploring pathways that link high dietary sugar to loss Sns. We will use deficiencies in a genetic approach to identifying novel regulators and expanding our recently identified core pathway.

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