Loss of Prolyl-Hydroxylase 1 Protects against Biliary Fibrosis via Attenuated Activation of Hepatic Stellate Cells

Strowitzki, Moritz J.; Kirchberg, Johanna; Tuffs, Christopher; Schiedeck, Maximilian; Ritter, Alina S.; Biller, Marvin; Harnoss, Jonathan M.; Lasitschka, Felix; Schmidt, Thomas; Radhakrishnan, P.; Ulrich, Alexis; Schneider, Martin

doi:10.1016/j.ajpath.2018.08.003

Cited by 17 publications

(12 citation statements)

References 46 publications

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“…For quantification of HIF-1α protein levels we used a commercially available enzyme-linked immunosorbent assay (ELISA kit, Abcam) detecting DNA binding activity as described before (51). HIF-1α levels were assessed in tissue lysates from anastomotic colonic biopsies harvested from vehicle-and DMOG-treated animals exposure.…”

Section: Detection Of Hif-1 Protein Levelsmentioning

confidence: 99%

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Strowitzki¹,

Kimmer²,

Wehrmann³

et al. 2021

JCI Insight

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Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD-deficiency (Phd1 -/-, Phd2 +/-, and Phd3 -/-) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2-haplodeficiency (Phd2 +/-) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2 +/-(but not PHI or Phd1 -/-) protected from sepsis-related mortality. Mechanistically, PHI and Phd2 +/induced immuno-modulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by Phd2 +/--mediated M2 polarization of macrophages, conferring a favourable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.

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Section: Detection Of Hif-1 Protein Levelsmentioning

confidence: 99%

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Strowitzki¹,

Kimmer²,

Wehrmann³

et al. 2021

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“…HIF-1α activation also upregulated miR-29c, which reduced renal interstitial fibrosis in a rat remnant kidney model [ 62 ]. Inhibition of fibrosis by PHIs may also occur independently of the HIF pathway [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats

et al. 2021

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Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.

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“…Hypoxia and HIFs have been acknowledged as important drivers of liver fibrosis (Strowitzki et al, 2018). In fact, hypoxia is involved in a variety of liver diseases.…”

Section: Role Of the Hif Pathway In Liver Fibrosismentioning

confidence: 99%

“…HIF-1α, activated in hypoxia, could regulate the transcription of many genes (Kietzmann, 2019). Increasing evidence shows the role of HIF-1α in the process of liver fibrosis (Strowitzki et al, 2018). On the other hand, it always shows excess oxidative stress, mitochondrial dysfunction, and excessive inflammation in chronic liver diseases.…”

Section: Introductionmentioning

confidence: 99%

Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis?

Zhang

Wang

et al. 2022

Front. Mol. Biosci.

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According to the WHO, “cirrhosis of the liver” was the 11th leading cause of death globally in 2019. Many kinds of liver diseases can develop into liver cirrhosis, and liver fibrosis is the main pathological presentation of different aetiologies, including toxic damage, viral infection, and metabolic and genetic diseases. It is characterized by excessive synthesis and decreased decomposition of extracellular matrix (ECM). Hepatocyte cell death, hepatic stellate cell (HSC) activation, and inflammation are crucial incidences of liver fibrosis. The process of fibrosis is also closely related to metabolic and immune disorders, which are usually induced by the destruction of oxygen homeostasis, including mitochondrial dysfunction, oxidative stress, and hypoxia pathway activation. Mitochondria are important organelles in energy generation and metabolism. Hypoxia-inducible factors (HIFs) are key factors activated when hypoxia occurs. Both are considered essential factors of liver fibrosis. In this review, the authors highlight the impact of oxygen imbalance on metabolism and immunity in liver fibrosis as well as potential novel targets for antifibrotic therapies.

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Loss of Prolyl-Hydroxylase 1 Protects against Biliary Fibrosis via Attenuated Activation of Hepatic Stellate Cells

Cited by 17 publications

References 46 publications

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats

Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis?

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