Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury

Xie, Dengpiao; Wang, Juan; Hu, Gaizun; Chen, Chaoling; Ritter, Joseph K.; Qu, Yun; Li, Ningjun

doi:10.1124/jpet.121.000667

Cited by 12 publications

(8 citation statements)

References 63 publications

(81 reference statements)

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“…Renal function was determined by the levels of plasma creatinine and BUN by using LabAssay Creatinine kit (Fujifilm, Japan) and Vet Axcel Chemistry Analyzer (Alfa Wassermann, NJ) with Urea Nitrogen Reagent Kit, respectively (Xie et al, 2021;Chen et al, 2022a).…”

Section: Renal Function Analysismentioning

confidence: 99%

“…Immunohistochemistry on paraffin-embedded kidney sections was performed as previously reported (Xie et al, 2021;Chen et al, 2022a). In brief, paraffin-embedded sections were deparaffinized and followed by subsequent antigen retrieval, endogenous peroxidase blocking with 3% H 2 O 2 , and nonspecific sites blocking in 10% serum.…”

Section: Immunohistochemical (Ihc) Staining In Kidney Tissuesmentioning

confidence: 99%

“…Scoring of tubular injuries was semi-quantitatively assessed by two blinded evaluators blinded to treatment. At least 10 fields were obtained from a microscope (200-fold magnification) for the measurement of kidney tubular cast area by using ImageJ (Xie et al, 2021;Chen et al, 2022a).…”

Section: Histological Examination By Periodic-acid Schiff Stainingmentioning

confidence: 99%

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Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Chen¹,

Wang²,

Raymond³

et al. 2023

Molecular Pharmacology

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Cisplatin is a potent first-line therapy for many solid malignancies such as breast, ovarian, lung, testicular and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits antiinflammatory effects; however, little is known about its role in cisplatin nephrotoxicity.The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatininduced AKI. Male wild-type C57BL6 (WT) and Faah −/− mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later.Faah −/− mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (PEA and OEA), attenuated NF-κB/p65 activity, DNA damage markers p53, p21 and decreased expression of the inflammatory cytokine IL-1β as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity.

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Section: Renal Function Analysismentioning

confidence: 99%

Section: Immunohistochemical (Ihc) Staining In Kidney Tissuesmentioning

confidence: 99%

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Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Chen¹,

Wang²,

Raymond³

et al. 2023

Molecular Pharmacology

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“…Furthermore, systemic HIF activation by VHL loss or xenon-mediated enhanced translation ameliorated AKI [19, 20]. HIF activation limited to the kidney by nanoparticle-based targeted delivery of PHD2 siRNA was sufficient to protect against IRI [21]. Accordingly, VHL deletion restricted to the thick ascending limb conveyed substantial protection against ischemic kidney injury elucidating the importance of this nephron segment [22].…”

Section: Hif Activation Protects Against Acute Kidney Injurymentioning

confidence: 99%

Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Tiwari¹,

Kapitsinou²

2021

Nephron

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Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

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“…Drug nanoformulation is a viable option for improving the on-target tissue accumulation of drugs [ 37 , 38 ]. Recently, a relevant study demonstrated that, in a mouse model of acute kidney injury, the intravenous injection of polyamidoamine dendrimer-wrapped PHD2 siRNA nanoparticles with folate decoration results in nanoparticle accumulation most in the kidneys and significantly reduces reperfusion injury [ 39 ]. To date, however, the nanoformulation of PHD inhibitors remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α

Jian

Gao

et al. 2022

Nanomaterials

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Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

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Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury

Cited by 12 publications

References 63 publications

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α

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