Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis

Wei, Xuejiao; Zhu, Xiaoyu; Jiang, Lili; Huang, Xiu; Zhang, Yangyang; Zhao, Dan; Du, Yujun

doi:10.1007/s11255-020-02474-2

Cited by 21 publications

(15 citation statements)

References 69 publications

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“…HIF-1α is a transcription factor that is widely present in the cytoplasm and nucleus and can indicate the degree of hypoxia. 37 The trend of the HIF-1α score was similar to that of the HE score of renal tubular injury. This also reflects the direct consequence of hypoxia caused by reduced perfusion.…”

Section: Discussionsupporting

confidence: 54%

Perfusion Analysis of Kidney Injury in Rats With Cirrhosis Induced by Common Bile Duct Ligation Using Arterial Spin Labeling MRI

Xie

Wang

et al. 2021

Magnetic Resonance Imaging

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Background Arterial spin labeling (ASL) has been proven to be effective in ischemia‐induced acute kidney injury (AKI); however, validation of ASL magnetic resonance imaging (MRI) is limited in AKI in the presence of cirrhosis. Purpose To investigate the feasibility of ASL in revealing renal blood flow (RBF) changes in kidney injury in the presence of cirrhosis and to assess its value in the early diagnosis of disease. Study Type Longitudinal. Animal Model Rats were randomized into baseline group (N = 3), sham surgery group (N = 18), and common bile duct ligation (BDL) group (N = 48). All groups were divided into six subgroups based on different sacrificed time points. Field Strength/Sequence 3 T scanner, prototypic pulsed ASL sequence using flow‐sensitive alternating inversion recovery preparation, half‐Fourier acquisition single‐shot turbo spin echo sequence. Assessment RBF measurement was performed by ASL. Hematoxylin–eosin (HE) score, Hypoxia‐inducible factor‐1alpha (HIF‐1α) score, peritubular capillar (PTC) density, alanine aminotransferase, aspartate aminotransferase, serum total bilirubin, total bile acids, serum creatinine (Scr), and blood urea nitrogen (BUN) were harvested. Statistical Tests Analysis of variance, Pearson's correlation coefficient, and receiver operating characteristic curves were performed. P < 0.05 was considered statistically significant. Results RBF, HE score, HIF‐1α score, and PTC density after BDL were significantly different from baseline. RBF was highly correlated with HE score, HIF‐1α score, and PTC density (r = −0.7598, r = −0.7434, r = 0.6406, respectively). RBF and Scr began to differ significantly from baseline at day 3 and 7 after intervention, respectively. The areas under the curves of RBF, Scr, and BUN for distinguishing non‐AKI from AKI in cirrhosis were 1.00, 0.888, and 0.911, while those for distinguishing mild from severe kidney injury were 0.961, 0.830, and 0.857, respectively. Data Conclusion ASL allows the longitudinal assessment of the degree of AKI induced by cholestatic cirrhosis in rats and can serve as a noninvasive marker for the early and accurate diagnosis of AKI. Level of Evidence 2 Technical Efficacy Stage 2

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Section: Discussionsupporting

confidence: 54%

Perfusion Analysis of Kidney Injury in Rats With Cirrhosis Induced by Common Bile Duct Ligation Using Arterial Spin Labeling MRI

Xie

Wang

et al. 2021

Magnetic Resonance Imaging

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“…Rajendran et al [49] found that in IR-induced AKI model of mouse, HIF-1 activated by inhibiting the PHD2 in RTECs could improve renal in ammation as well as renal failure and block the transition from AKI to CKD. On the other hand, there are also some evidences indicating that in the context of hypoxia, HIF-1α could induce EMT of RTECs and ECM deposition to promote the occurrence of renal brosis [3,15]. For example, Higgins et al [50] found that in the models of mice with UUO-induced renal injury and proximal RTECs with hypoxia-induced injury in vitro, HIF-1α could promote the EMT of RTECs while genetic ablation of HIF-1α in RTECs could inhibit the development of renal tubulointerstitial brosis, which might be related to the decrease of interstitial collagen deposition, in ammatory cell in ltration and broblast-speci c protein-1-expressing (FSP-1-expressing) interstitial cells.…”

Section: Discussionmentioning

confidence: 99%

“…In hypoxia, the activity of PHDs is inhibited to prevent the hydroxylation and hydrolysis of HIF-1α, resulting in the accumulation of HIF-1α. HIF-1α interacts with HIF-1β to form a dimer HIF-1 and then HIF-1 binds to hypoxia response elements (HRE) in the regulatory region of the nucleus to activate downstream target genes, such as Erythropoietin (EPO), vascular endothelial growth factor (VEGF), Twist and B lymphoma Mo-MLV insertion region homolog 1 (Bmi1), eventually inducing related hypoxia responses like angiogenesis, cell proliferation and apoptosis [3,13,[15][16][17]. At present, more and more studies have found that HIF-1α may be one of the key regulators of renal tubular hypoxia injury and renal brosis [3,15,17,18].…”

Section: Introductionmentioning

confidence: 99%

Protective effects of MSC-conditioned medium on DFO-induced mimetic-hypoxia injury of renal tubular epithelial cells

Zhou

Liao

Weng

et al. 2022

Preprint

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Background: Acute kidney injury (AKI) is mainly characterized by inflammatory infiltration, the damage and death of renal tubular epithelial cells (RTECs), in which hypoxia plays an important role. Deferoxamine (DFO) inducing cells’ mimetic-hypoxia injury is a well-accepted renal injury model in vitro. Mesenchymal stem cell - conditioned medium (MSC-CM) can reduce local inflammation and repair tissue. In this study, we explored the effect of MSC-CM on RTECs under DFO mimetic-hypoxia and its possible molecular mechanism. Methods: NRK-52E cells with the treatment of DFO25uM for 24 hours could be well-accepted RTECs’ injury model using Cell Counting Kit-8 (CCK-8) to detect cell viability and Western Blot to evaluate the expression of transforming growth factor-beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), hypoxia-inducible factor-1 alpha (HIF-1α) in NRK-52E cells with the treatment of different concentrates of DFO for 24 hours. Then three groups of NRK-52E cells were used in experiments, including normal control (NC), DFO25uM, DFO25uM+MSC-CM. MSC-CM was used to culture cells for 12 hours before DFO treatment, then fresh MSC-CM and DFO 25uM cocultured cells for another 24 hours. Then the cell samples were collected. Results: Using Western Blot and cellular immunofluorescence, we found MSC-CM could reverse the DFO-induced up-regulation of TGF-β1, α-SMA, HIF-1α and steroid receptor coactivator 1 (SRC-1). DFO 25uM coculturing NRK-52E cells for 24 hours could simulate hypoxia well; HIF-1α and SRC-1 might be the harmful factors promoting EMT in NRK-52E cells during DFO mimetic-hypoxia.Conclusions: Our results suggest that MSC-CM have a protective effect on RTECs under DFO mimetic-hypoxia by down-regulating HIF-1α and SRC-1 which may be the harmful factors in renal injury.

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“…Fourth, we did not consider the use of erythropoiesis-stimulating agents during the follow-up period. As to treatment contents, recent studies have revealed that hypoxia-inducible factor-prolyl hydroxylase inhibitors might suppress tubulointerstitial fibrosis by suppressing the transformation of renal interstitial fibroblasts in addition to enhancing erythropoiesis [ 27 , 28 ]. Furthermore, some previous studies revealed that sodium-glucose cotransporter 2 inhibitors might improve tubulointerstitial hypoxia, allowing fibroblasts to resume erythropoietin production [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

et al. 2021

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Background Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. Methods A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. Results At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. Conclusions Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

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Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis

Cited by 21 publications

References 69 publications

Perfusion Analysis of Kidney Injury in Rats With Cirrhosis Induced by Common Bile Duct Ligation Using Arterial Spin Labeling MRI

Perfusion Analysis of Kidney Injury in Rats With Cirrhosis Induced by Common Bile Duct Ligation Using Arterial Spin Labeling MRI

Protective effects of MSC-conditioned medium on DFO-induced mimetic-hypoxia injury of renal tubular epithelial cells

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

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