Thesis topic proposal
László Rosivall
Novel Concepts in the Regulation of Blood Pressure and Kidney Function


Institute: Semmelweis University, Budapest
theoretical medicine
Doctoral School of Basic and Translational Medicine

Thesis supervisor: László Rosivall
Location of studies (in Hungarian): Kórélettani Intézet
Abbreviation of location of studies: SE

Description of the research topic:

The ongoing research program is focusing on key molecular, cellular and (patho)physiological regulatory mechanisms within the kidney that maintain body fluid and electrolyte homeostasis and systemic blood pressure in health and disease. Our broad, long-term objective is to make clinically important, translatable discoveries in basic science that can be used to develop novel therapeutic strategies for the better treatment of high blood pressure and renal disease. Specifically, we study the function of the juxtaglomerular apparatus (JGA), an important cell complex in the kidney and the regulation of the renin-angiotensin system (RAS), as key regulatory sites of renal blood flow, glomerular filtration rate (GFR), renal salt & water conservation and blood pressure maintenance. We investigate the activation and regulatory mechanisms of the RAS in the pathogenesis of hypertension and diabetic nephropathy. One of the most exciting new directions in our lab is the study of metabolic control, role of metabolic byproducts, Krebs-cycle intermediates in renin release, the rate-limiting step of RAS activation in association with epidemic metabolic diseases like diabetes mellitus and metabolic syndrome.
Our ongoing work in the lab is currently being extended to the whole organ and animal level using a number of disease models and a novel imaging approach. This new innovation is consistent with our philosophy of integrative, multi-level (molecular, cellular, tissue, organ, and whole animal) and translational research. Recently, my laboratory pioneered the in vivo application of a state-of-the-art imaging technology called multi-photon fluorescence microscopy to directly visualize and quantify basic parameters of kidney function. In fact, our work is renowned largely due to the use of this imaging approach as evidenced by recent journal cover images, invited seminars and reviews. Direct, real-time visualization and quantification of glomerular filtration rate, blood flow, tubular function, renin release and tissue activity with high temporal and spatial resolution combined with simultaneous monitoring of systemic blood pressure and plasma glucose provides a complex tool and survey of renal (patho)physiology. Ongoing and future studies funded by NIDDK focus on the mechanism of RAS activation by metabolic intermediates, most importantly succinate and uric acid. We started studying the role of the newly identified (pro)renin receptor in RAS activation and in the pathogenesis of diabetic complications funded by the American Heart Association.
Using multi-photon imaging, we obtained several novel and provocative findings. For example, direct visualization of renin release, the rate-limiting step of RAS activation in the living diabetic kidney helped us to challenge existing paradigms on the pathogenesis of diabetic nephropathy and associated hypertension. In recent work we found that increasing glucose levels quickly and directly act on a newly identified, kidney-specific metabolic receptor (GPR91) in the vascular endothelium and acutely trigger renin release and elevations in blood pressure via accumulating glucose metabolites (succinate), and not through systemic effects or other indirect feedback mechanisms. Because of the central role of renin activation in early diabetes, we are testing the anti-hypertensive and renal effects of the novel renin inhibitor aliskiren.

Number of students who can be accepted: 3

Deadline for application: 2019-12-31

All rights reserved © 2007, Hungarian Doctoral Council. Doctoral Council registration number at commissioner for data protection: 02003/0001. Program version: 2.2358 ( 2017. X. 31. )