Study Purpose: Renal fibrosis is a failure of regenerative mechanisms; strategies aimed towards identifying suitable targets for fibrotic tissue may hold promise in mitigating or preventing progressive fibrosis thereby reducing the need for renal replacement therapy and critical organ shortage.
Methods: Since type II macrophages are a crucial component of regeneration, our experiments were designed to test nanoparticle delivery of GM-CSF, known to recruit macrophages, and IL-10, known to convert inflammatory macrophages to suppressive, phagocytic type II macrophages capable of clearing debris, initiating matrix deposition, and delivering pro-angiogenic signals. We compared targeting molecules EGF (richly expressed in the kidney) and FSP1 (Fibroblast specific protein 1, known to be expressed following kidney injury) for their ability to deliver either GM-CSF or IL-10 payload after an acute ischemic insult induced by unilateral murine renal pedicle ligation. Since injured vasculature enables nanoparticle delivery to sites of injury, we hypothesized that injured tissue would garner more nanoparticle deposition. Delivery of either IL-10 or GM-CSF nanoparticles or cytokine alone was compared between injured and uninjured kidneys with and without targeting molecules EGF and FSP1.
Results: With FSP1 targeting, we observed higher IL-10 levels compared to EGF targeting in the injured kidney (190-fold higher) and compared to IV IL-10 alone (206-fold higher). Injured kidneys treated with EGF-targeted GM-CSF nanoparticles had lower levels of GM-CSF (1.29×104 pg/mL/pg total protein) than serum (3.24×104 pg/mL/pg total protein) or in uninjured kidney (1.76×104 pg/mL/pg total protein).
Conclusions: FSP1 targeting provides superior IL-10 and GM-CSF delivery in the acutely injured kidney. A paradoxical drop of GM-CSF observed in the injured kidney may be due to increased delivery and subsequent endocytosis by infiltrating macrophages found in the acutely injured kidney. These studies support extension of investigation into the functional responses induced by this targeted nanoparticle payload delivery system.
Bartholomew, A.: Other, LNK Chemsolutions, Medical Consultant.
To cite this abstract in AMA style:Tobin M, O'Connor M, Szilagyi E, Capezio N, Nuñez L, Spretz R, Noriega S, Bartholomew A. Effect of EGF and FSP1 Targeting of Nanoparticle Delivery of IL-10 and GM-CSF Following Acute Kidney Injury, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/effect-of-egf-and-fsp1-targeting-of-nanoparticle-delivery-of-il-10-and-gm-csf-following-acute-kidney-injury-the/. Accessed October 31, 2020.
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