ResearchIn-Press PreviewNephrology
Open Access | 10.1172/jci.insight.177775
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
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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
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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
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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
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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
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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
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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
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Published September 3, 2024 - More info
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.