J Pharmacol Exp Ther. 2025 Dec;392(12):103556. doi: 10.1016/j.jpet.2025.103556.
ABSTRACT
Renal fibrosis is the hallmark and final common pathway of chronic kidney disease. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that cleave bioactive molecules to maintain extracellular matrix homeostasis. MMP-2 is upregulated in the progression of fibrosis in several models. We hypothesized that a renal-targeted MMP-2 inhibitor can slow the progression of renal fibrosis in a model of hypertension-induced renal injury. An MMP-2 inhibitory protein therapeutic was developed by fusing a known peptide inhibitor of MMP-2 (MMP-2i) to the elastin-like polypeptide (ELP) drug delivery system. Three sizes of the ELP carrier were tested to optimize the fusion protein's in vitro and in vivo performance. Activity and specificity of ELP-MMP-2i constructs for inhibition of MMP-2 were determined using in vitro MMP assays. Plasma clearance, organ biodistribution, renal accumulation, and intrarenal distribution of the fusion proteins were measured after intravenous and subcutaneous administration. The efficacy of the lead ELP-MMP-2i protein was determined using the Dahl salt-sensitive rat model of renal injury. A potent and selective inhibition of MMP-2 by ELP-MMP-2i was observed, and the construct containing the smallest ELP domain was the most potent. All fusion proteins targeted the kidneys, with the smallest fusion protein having the highest bioavailability after subcutaneous delivery. Efficacy studies with the optimized ELP-MMP-2i protein revealed that ELP-MMP-2i treatment reduced proteinuria, albuminuria, and renal fibrosis compared with vehicle-treated hypertensive rats. Renally targeted delivery of an MMP-2 inhibitor using the novel ELP drug delivery system has the potential to prevent hypertension-induced renal fibrosis and could represent a future therapy for chronic kidney disease. SIGNIFICANCE STATEMENT: To the authors' knowledge, this is the first study to demonstrate the ability of a kidney-targeted selective matrix metalloproteinase-2 inhibitory peptide biologic to reduce renal fibrosis in a renal injury model.
PMID:41478668 | DOI:10.1016/j.jpet.2025.103556