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Abstract
The G protein–coupled CXC chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define its renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, TGF-β1 expression, and fibroblast activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-β1–induced upregulated expression of ECM, matrix metalloproteinase-2, and downstream p38 mitogen-activated protein kinase (p38 MAPK) and PI3K/AKT/mTOR signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.
Highlights
Fibrosis is a pathologic variant of the normal wound healing process characterized by injury, inflammation, myofibroblast activation, and matrix accumulation and remodeling [1]
CXCR4 is highly expressed in the embryonic kidney, its expression is significantly lower in healthy adult kidneys [8, 24]
These data indicated that CXCR4 expression is upregulated significantly in humans with diabetic kidney disease (DKD) and in 3 fibrotic mouse models, of which folic acid (FA) nephropathy had the highest increase in CXCR4 expression
Summary
Fibrosis is a pathologic variant of the normal wound healing process characterized by injury, inflammation, myofibroblast activation, and matrix accumulation and remodeling [1]. Fibrotic diseases have been estimated to account for up to half of deaths in the developed world [2]. There is no clinically satisfactory therapeutic approach to fibrosis. Chronic kidney disease (CKD) is an epidemic increasing at an alarming rate [3]. Kidney fibrosis is the major contributor to progression of almost all forms of CKD [4]. Despite many attempts to block kidney fibrosis, few have been approved in clinical practice and a large treatment gap remains. Novel anti-fibrotic therapies are urgently needed to prevent the progression of kidney fibrosis in CKD
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