Sparsentan improves glomerular hemodynamics, cell functions, and tissue repair in a mouse model of FSGS
Georgina Gyarmati, Urvi Nikhil Shroff, Audrey Izuhara, Sachin Deepak, Radko Komers, Patricia W. Bedard, Janos Peti-Peterdi
Georgina Gyarmati, Urvi Nikhil Shroff, Audrey Izuhara, Sachin Deepak, Radko Komers, Patricia W. Bedard, Janos Peti-Peterdi
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Research Article Nephrology

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

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 with current standard of care using angiotensin receptor blockers (ARBs). 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 and 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; and 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 with 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.

Authors

Georgina Gyarmati, Urvi Nikhil Shroff, Audrey Izuhara, Sachin Deepak, Radko Komers, Patricia W. Bedard, Janos Peti-Peterdi

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Figure 6

Effects of sparsentan and losartan on podocyte number, glomerulosclerosis and tissue fibrosis, and endogenous tissue regeneration in FSGS.

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Effects of sparsentan and losartan on podocyte number, glomerulosclerosi...
(A and B) p57 (A) or WT1 (B) immunolabeling (red, arrowheads) and statistical summary of p57+ or WT1+ podocyte number/glomerulus in fixed histological sections from no-drug control (left), sparsentan-treated (center), and losartan-treated (right) treated (for 6 weeks) Pod-GCaMP5/tdTomato TRPC6-Tg mouse (1.5 years old) kidneys (n = 8 each). Tissue autofluorescence is shown in yellow. (C) Picrosirius red (red) staining of kidney sections from the same groups/mice as in A, and glomerulosclerosis index (based on Picrosirius red density per glomeruli) and tissue fibrosis index (based on Picrosirius red density per full image frame) in the various treatment groups (n = 8 each). (D–G) Clonal analysis of Ren1d-Confetti (D) and Cdh5-Confetti (E) Pod-TRPC6-Tg mouse (6 months old) kidneys from same treatment groups as shown in A (n = 8 each). Note the presence of the genetically encoded multicolor Confetti reporter (CFP [blue], GFP [green], YFP [yellow], and RFP [red]) in cells of the renin lineage (D) or vascular endothelium (E) and entirely clonal (identical color) glomeruli (yellow/magenta/blue arrows) in sparsentan-treated mice (C, center), and to a lower extent in losartan-treated mice (C, right). Statistical summary of the number of Confetti+ cells, identical color cell groups, cells per clone and clone frequency (F and G) in the various treatment groups in Ren1d-Confetti (D and F) and Cdh5-Confetti mice (E and G). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 using 1-way ANOVA with Tukey’s multiple-comparison test. NS, not significant. For all panels, n = 10 measurements averaged for each of the n = 8 mice (n = 4 males [blue] and n = 4 females [red]) in each group. G, glomerulus. Scale bars: 20 μm.