Advertisement

ResearchIn-Press PreviewNephrology Open Access | 10.1172/jci.insight.177775

Sparsentan improves glomerular hemodynamics, cell functions and tissue repair in a mouse model of FSGS

Georgina Gyarmati,1 Urvi Nikhil Shroff,1 Audrey K. Izuhara,1 Sachin Deepak,1 Radko Komers,2 Patricia W. Bedard,2 and Janos Peti-Peterdi1

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Gyarmati, G. in: JCI | PubMed | Google Scholar

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Shroff, U. in: JCI | PubMed | Google Scholar

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Izuhara, A. in: JCI | PubMed | Google Scholar

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Deepak, S. in: JCI | PubMed | Google Scholar

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Komers, R. in: JCI | PubMed | Google Scholar

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Bedard, P. in: JCI | PubMed | Google Scholar

1Departments of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

2Travere Therapeutics, San Diego, United States of America

Find articles by Peti-Peterdi, J. in: JCI | PubMed | Google Scholar |

Published September 3, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.177775.
Copyright © 2024, Gyarmati et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 3, 2024 - Version history
View PDF
Abstract

Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive compared to current standard of care using angiotensin receptor blockers (ARB). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters, increased or preserved blood flow and single nephron glomerular filtration rate, attenuated acute ET-1+AngII-induced increases in podocyte calcium, reduced proteinuria, preserved podocyte number, increased both endothelial and renin lineage cells and clones in vasculature, glomeruli and tubules, restored glomerular endothelial glycocalyx, attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared to losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.

Graphical Abstract
graphical abstract
Supplemental material

View Supplement Video 1

View Supplement Video 2

Version history
  • Version 1 (September 3, 2024): In-Press Preview
Advertisement
Advertisement