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Abstract
Fibrosis is a final common pathway for many causes of progressive chronic kidney disease (CKD). Arginine–glycine–aspartic acid (RGD)‐binding integrins are important mediators of the pro‐fibrotic response by activating latent TGF‐β at sites of injury and by providing myofibroblasts information about the composition and stiffness of the extracellular matrix. Therefore, blockade of RGD‐binding integrins may have therapeutic potential for CKD. To test this idea, we used small‐molecule peptidomimetics that potently inhibit a subset of RGD‐binding integrins in a murine model of kidney fibrosis. Acute kidney injury leading to fibrosis was induced by administration of aristolochic acid. Continuous subcutaneous administration of CWHM‐12, an RGD integrin antagonist, for 28 days improved kidney function as measured by serum creatinine. CWHM‐12 significantly reduced Collagen 1 (Col1a1) mRNA expression and scar collagen deposition in the kidney. Protein and gene expression markers of activated myofibroblasts, a major source of extracellular matrix deposition in kidney fibrosis, were diminished by treatment. RNA sequencing revealed that inhibition of RGD integrins influenced multiple pathways that determine the outcome of the response to injury and of repair processes. A second RGD integrin antagonist, CWHM‐680, administered once daily by oral gavage was also effective in ameliorating fibrosis. We conclude that targeting RGD integrins with such small‐molecule antagonists is a promising therapeutic approach in fibrotic kidney disease.
Highlights
Chronic kidney disease (CKD) affects ~15% of the population
We examined the effect of CWHM-12 treatment on kidney fibrosis in a nephrotoxic model of acute kidney injury
The number of intact proximal tubules was significantly greater in CWHM-12-treated kidneys at 27 days after AA induced injury compared with vehicle-treated animals (57.1 ± 1.7 vs. 40.9 ± 1.6, n = 5 for each group, p < .0001). These results demonstrated that inhibition of RGD integrins preserved intact proximal tubules, and ameliorated kidney fibrosis and renal dysfunction in a model of nephrotoxic kidney injury
Summary
Lee, Kim, & Choi, 2015), even after adjusting for eGFR, proteinuria, and clinicopathological diagnosis (Srivastava et al, 2018). Dampening the activity of these induced activated integrins is hypothesized to facilitate return to the homeostatic state without the systemic side effects that have been observed with indiscriminate global anti-TGF-β therapy Independent of their role in TGF-β activation, RGD-binding integrins are critical transducers of biomechanical force allowing cells to respond to matrix stiffness by promoting myofibroblast differentiation, migration, and survival (Fiore et al, 2018; Lampi & Reinhart-King, 2018; Santos & Lagares, 2018). Interference with these signals may alter myofibroblast numbers and/or functions in an incipient or ongoing disease state. To test the potential therapeutic utility of combined targeting of the subset of RGD-binding integrins implicated in pro-fibrotic molecular and cellular processes, we employed stable peptidomimetic small-molecule inhibitors of these integrins in an established nephrotoxic model of kidney fibrosis
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