Flow-stimulated ion channel signalling in renal epithelia

ended

The principal role of the kidneys is the critical regulation of our electrolyte balance, through an integrated system of reabsorption and secretion of fluid and electrolytes. Once blood is filtered in the glomeruli, renal electrolyte reabsorption rate has to be adjusted to the variable electrolyte load associated with fluctuations of the pro-urine flow. The variable flow of pro-urine results in changing fluid-shear stress (FSS) that activates mechanosensitive signalling pathways in the epithelial cells of the renal tubule. Hence, the kidney’s sensing ability adapts epithelial function to the dynamic tubular environment. Preliminary data from the host laboratory shows that polycystin-1 (PC1), a mechanosensitive entity in renal epithelia, is involved in the FSS-mediated signalling response by increasing the ATP release. Moreover, mice with a kidney-specific knockout of the PC1 encoding gene, Pkd1, exhibit significant electrolyte imbalances. The focus of the present project proposal is to elucidate how FSS modulates renal electrolyte handling by exploiting PC1-deficient renal cells and animal models. This will provide new insights into the flow-sensing mechanisms in the kidney. Specifically, the role of ATP-mediated signalling pathways in the regulation of ion channels and transporters in the distal part of the nephron will be investigated. To this end, the following work packages will be addressed: A) Control of electrolyte reabsorption by FSS. Assess the expression and function of FSS-regulated transporter proteins in Pkd1-/- cells. B) Translation of FSS into ATP signalling to regulate renal electrolyte handling. It is my aim to identify the downstream proteins involved in FSS-mediated ATP signalling and decipher their role in electrolyte handling in vivo. Taken together, this project focuses on the FSS-mediated signalling pathways. The goal is to elucidate the regulation exerted on ion channels and transporters linking the variable flow-rate of the pro-urine