Abstract
Renal fibrosis, a hallmark of chronic kidney disease (CKD), is characterized by excessive deposition of extracellular matrix (ECM) components. Human and animal studies have shown that upregulation of the endopeptidase matrix metalloproteinase-2 (MMP-2) cleaves ECM and cytokines to promote inflammation and fibrosis in CKD. The objective of this study is to develop a novel, kidney-targeted MMP-2 inhibitor for prevention of renal fibrosis. Our group fused an MMP-2 inhibitory peptide (MMP-2i) to a kidney targeting biopolymer known as elastin like polypeptide (ELP). We previously optimized renal targeting of ELP-MMP-2i by testing the effect of ELP molecular weight on renal deposition and renal specificity, resulting in the selection of ELP 63 -MMP-2i (an ELP with 63 pentapeptide repeats and a molecular weight of 25 kDa) as a lead agent for continued therapeutic development. We also previously validated that ELP 63 -MMP-2i specifically inhibits MMP-2 without affecting other MMPs expressed in the kidney. The hypothesis of the current study is that our optimized agent, ELP 63 -MMP-2i, will ameliorate renal injury when administered to Dahl salt sensitive (Dahl S) rats fed a high-salt diet. To assess the efficacy of our therapeutic, 12-week-old Dahl S rats (male, n=4 per group) were fed a high salt (8% NaCl) diet and simultaneously dosed (300 nmol/kg/day s.c.) with either vehicle or ELP 63 -MMP-2i for 3 weeks. Metabolic cage housing was performed weekly to collect urine, blood pressure was assessed in conscious rats weekly by tail cuff plethysmography and at the experimental endpoint by direct measurement via an arterial catheter, and renal histology was assessed by Masson trichrome staining. Neither high-salt diet or ELP 63 -MMP-2i had any effect on the rats’ body weight. Blood pressure was elevated in Dahl S rats fed a high-salt diet (one-way ANOVA, F(2,19) time = 28.95, p<0.0001), and ELP 63 -MMP-2i had no effect on the blood pressure elevation (F(2,9) treatment = 0.03, p=0.97). Proteinuria was also significantly and progressively elevated during the high-salt feeding period (F(2,19) time = 15.61, p<0.0001). ELP 63 -MMP-2i treatment reduced the severity of proteinuria (F(2,9) treatment = 5.02, p=0.03). We also observed significant renal fibrosis in Dahl S rats after 21 days of high-salt diet, and that there was a trend for reduced fibrosis in the renal cortex in rats treated with ELP 63 -MMP-2i compared to vehicle (paired t-test, p=0.11). These are intermediate findings of an ongoing study with a planned enrollment of 8 rats per group. The intermediate analysis suggests that inhibiting MMP-2 activity with an MMP-2 specific and renally targeted biologic is renoprotective and may be beneficial as a treatment for CKD. This work was supported by NIH grants R01HL095638 to GLB, R01HL138685 to RJR and F31DK130598 to AAA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Published Version
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