Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization

Engel, Jason; Williams, Erika; Williams, Maxx; BidwellIII, Gene L.; Chade, Alejandro

doi:10.1161/hypertensionaha.119.13469

Cited by 46 publications

(55 citation statements)

References 63 publications

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“…To overcome some of these limitations, we first developed an ELP fusion protein with human VEGF-A 121 [29], the smallest, non-heparin-binding form of VEGF-A [44,45]. In extensive preclinical testing, the therapeutic potential of the ELP–VEGF fusion protein was demonstrated for treatment of kidney disease, including renal artery stenosis-induced renovascular disease [36,46,47] and chronic kidney disease [48]. These models, as observed in humans with these diseases, displayed a progressive loss of renal function associated with extensive microvascular rarefaction and renal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

2019

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Elastin-like polypeptides (ELP) are versatile protein biopolymers used in drug delivery due to their modular nature, allowing fusion of therapeutics and targeting agents. We previously developed an ELP fusion with vascular endothelial growth factor (VEGF) and demonstrated its therapeutic efficacy in translational swine models of renovascular disease and chronic kidney disease. The goal of the current work was to refine renal targeting and reduce off-target tissue deposition of ELP–VEGF. The ELP–VEGF fusion protein was modified by adding a kidney-targeting peptide (KTP) to the N-terminus. All control proteins (ELP, KTP–ELP, ELP–VEGF, and KTP–ELP–VEGF) were also produced to thoroughly assess the effects of each domain on in vitro cell binding and activity and in vivo pharmacokinetics and biodistribution. KTP–ELP–VEGF was equipotent to ELP–VEGF and free VEGF in vitro in the stimulation of primary glomerular microvascular endothelial cell proliferation, tube formation, and extracellular matrix invasion. The contribution of each region of the KTP–ELP–VEGF protein to the cell binding specificity was assayed in primary human renal endothelial cells, tubular epithelial cells, and podocytes, demonstrating that the VEGF domain induced binding to endothelial cells and the KTP domain increased binding to all renal cell types. The pharmacokinetics and biodistribution of KTP–ELP–VEGF and all control proteins were determined in SKH-1 Elite hairless mice. The addition of KTP to ELP slowed its in vivo clearance and increased its renal deposition. Furthermore, addition of KTP redirected ELP–VEGF, which was found at high levels in the liver, to the kidney. Intrarenal histology showed similar distribution of all proteins, with high levels in blood vessels and tubules. The VEGF-containing proteins also accumulated in punctate foci in the glomeruli. These studies provide a thorough characterization of the effects of a kidney-targeting peptide and an active cytokine on the biodistribution of these novel biologics. Furthermore, they demonstrate that renal specificity of a proven therapeutic can be improved using a targeting peptide.

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Section: Introductionmentioning

confidence: 99%

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

2019

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“…The decrease in VEGF has been previously associated with the development of hypertension and significant loss of podocytes, aggravating the progression of kidney damage [ 52 , 53 , 54 ]. Indeed, some authors propose that VEGF therapy could promote renal microvascular repair to reverse rarefaction responses [ 55 , 56 ]. Here, we show that opioid preconditioning promoted VEGF protein expression directly in the left ischemic kidney, indicating activation of proangiogenic responses aimed at reducing microvascular loss.…”

Section: Discussionmentioning

confidence: 99%

Opioid Preconditioning Modulates Repair Responses to Prevent Renal Ischemia-Reperfusion Injury

et al. 2020

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Progression to renal damage by ischemia-reperfusion injury (IRI) is the result of the dysregulation of various tissue damage repair mechanisms. Anesthetic preconditioning with opioids has been shown to be beneficial in myocardial IRI models. Our main objective was to analyze the influence of pharmacological preconditioning with opioids in renal function and expression of molecules involved in tissue repair and angiogenesis. Experimental protocol includes male rats with 45 min ischemia occluding the left renal hilum followed by 24 h of reperfusion with or without 60 min preconditioning with morphine/fentanyl. We analyzed serum creatinine and renal KIM-1 expression. We measured circulating and intrarenal VEGF. Immunohistochemistry for HIF-1 and Cathepsin D (CTD) and real-time PCR for angiogenic genes HIF-1α, VEGF, VEGF Receptor 2 (VEGF-R2), CTD, CD31 and IL-6 were performed. These molecules are considered important effectors of tissue repair responses mediated by the development of new blood vessels. We observed a decrease in acute renal injury mediated by pharmacological preconditioning with opioids. Renal function in opioid preconditioning groups was like in the sham control group. Both anesthetics modulated the expression of HIF-1, VEGF, VEGF-R2 and CD31. Preconditioning negatively regulated CTD. Opioid preconditioning decreased injury through modulation of angiogenic molecule expression. These are factors to consider when establishing strategies in pathophysiological and surgical processes.

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“…Am J Nephrol 2020;51:891-902 DOI: 10.1159/000511260 Immunohistochemistry Midhilar kidney sections from each animal were stained for indoleamine-2,3-dioxygenase (IDO1; Invitrogen, 711778, 1/50) and mannose receptor c-type 1 (MRC1; LSBio, LS-B9805, 1/50) to identify M1 and M2 macrophages as previously described [12,26]. Slides were counterstained with the nuclear label DAPI.…”

Section: Ktp-elp-vegf In Renovascular Disease 893mentioning

confidence: 99%

“…How modulation of renal macrophage phenotype is mechanistically related to recovery of renal function following VEGF therapy is still unknown. Thus, the model of unilateral RVD offers the opportunity to extend our previous work [12] and test the hypothesis that long-term protective effects of KTP-ELP-VEGF therapy are mediated by a direct effect of VEGF to induce macrophages to an antiinflammatory, proangiogenic phenotype, leading to the recovery of renal MV architecture and function.…”

Section: Introductionmentioning

confidence: 99%

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Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease

Engel

Williams

et al. 2020

Am J Nephrol

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Background: Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. Methods: Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). Results: Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. Conclusions: Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.

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Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization

Cited by 46 publications

References 63 publications

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

Opioid Preconditioning Modulates Repair Responses to Prevent Renal Ischemia-Reperfusion Injury

Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease

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