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 4

Effects of sparsentan and losartan on glomerular hemodynamics and GFB function in FSGS.

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Effects of sparsentan and losartan on glomerular hemodynamics and GFB fu...
(A) Intravital MPM images of glomeruli (G) and their afferent (AA) and efferent (EA) arterioles from no-drug control (left), sparsentan-treated (center), and losartan-treated (right) Pod-GCaMP5/tdTomato TRPC6-Tg mice (1.5 years old). The circulating plasma was labeled by i.v. injected albumin–Alexa Fluor 680 (gray). Note the presence of the genetically encoded calcium reporter GCaMP5 (green) and the calcium-insensitive tdTomato (red) in podocytes. Podocytes with high calcium (intense green) are visible in a segmental pattern (arrows) adjacent to areas of adhesions between capillaries and parietal podocytes (arrowheads). Plasma albumin leaked through the GFB is visible in the Bowman’s space (asterisk). Scale bar: 20 μm. (B–J) Statistical summary of the measured hemodynamic and GFB parameters in the various treatment groups (n = 8 each), including podocyte calcium (based on the ratio of GCaMP5/tdTomato fluorescence [F] intensity, B), AA (C), EA (D), and glomerular diameters (E), glomerular tuft area (F), single-nephron glomerular filtration rate (SNGFR, G), glomerular capillary red blood cell velocity (H), albumin leakage through the GFB (based on albumin glomerular sieving coefficient [GSC], I), and albuminuria (based on urinary albumin/creatinine ratio [ACR] normalized to baseline, J). (K and L) Systolic blood pressure (BP) at baseline (K) and elevations (ΔBP) in response to acute AngII injection (L) (n = 8 each). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001 using 1-way ANOVA with Tukey’s multiple-comparison test. NS, not significant. For all panels, n = 10 measurements averaged for image-based parameters (panels B–I) for each of the n = 8 mice (n = 4 males [blue] and n = 4 females [red]) in each group.