The differential role of Hippo pathway signaling during hypertensive end-organ damage

• Applicant: Dr. Laura Katharina Sievers
• Subject Area: Nephrology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 439733899

Arterial hypertension is associated with severe cardiovascular complications and chronic damage of heart, kidney, vasculature and other organs. Hypertension is caused and sustained by a complex network of systemic signaling pathways, e.g. Angiotensin II and the renin- angiotensin- aldosterone system. Endothelium and immune cells are key cell types in the pathogenesis of microvascular end-organ damage. The balance of Th17 and Treg CD4+ lymphocyte subtypes modulates blood pressure and contributes to end- organ damage promoting a pro-inflammatory or immunotolerant phenotype. Further, endothelial remodeling and microvascular alterations are a hallmark of hypertensive end- organ complications.Interestingly, the Hippo pathway transcription factors TAZ and YAP are involved in the regulation of the Treg/ Th17 lymphocyte balance as well as in endothelial development and adaptations. The aim of the proposed project is to elucidate if and how the Hippo pathway modifies susceptibility to hypertensive end-organ damage, focusing on the effects on the endothelium and immune cells. Mice with conditional knockout and gain- of- function of the Hippo pathway transcription factors TAZ/ YAP in lymphocytes respectively endothelium will be phenotypically scrutinized in an Angiotensin II- based model of arterial hypertension. In this way, the significance of the transcription factor TAZ for lymphocyte differentiation and ultimately renal dysfunction in hypertensive kidney injury will be characterized and the pathogenetic role of endothelial Hippo signaling in hypertensive kidney injury will be elucidated in vivo. Further, the effect of the microenvironment on Angiotensin II signaling and Hippo pathway activity in lymphocytes and endothelial cells in vitro.

• DFG Programme: Research Grants