Detrimental effects of hypoxia on glomerular podocytes

Singh, Ashish; Kolligundla, Lakshmi P.; Francis, Justus; Pasupulati, Anil Kumar

doi:10.1007/s13105-021-00788-y

Cited by 18 publications

(23 citation statements)

References 87 publications

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“…According to mass spectrometry and network pharmacology, TSWN might prevent DN and decrease urinary albumin via the HIF-1a pathway. HIF-1a has a known association with DN, and could play a protective role in DN (6). Accumulating evidence reveals that elevated HIF-1a leads to DN and podocyte injury.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mainstream belief among scientists is that elevated HIF-1a is involved in the pathological process and proteinuria of glomerular diseases in DN. Podocyte damage may be susceptible to the accumulation of HIF-1a (6). In a previous work, increased HIF by knockout of prolyl hydroxylase domain protein-2 (PHD2), a factor degrading HIF, enhances renal fibrosis (7).…”

Section: Introductionmentioning

confidence: 97%

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TangShenWeiNing Formula Prevents Diabetic Nephropathy by Protecting Podocytes Through the SIRT1/HIF-1α Pathway

et al. 2022

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BackgroundDiabetic nephropathy (DN) represents a major complication of diabetes, and podocyte injury has a critical function in DN development. TangShenWeiNing formula (TSWN) has been demonstrated to efficiently decrease proteinuria and protect podocytes in DN. This work aimed to explore the mechanism by which TSWN alleviates DN and protects podocytes.MethodsThe major bioactive components of TSWN were detected by mass spectrometry (MS) and pharmacological databases. Eight-week-old male C57BLKS/J db/m and db/db mice were provided pure water, valsartan, low dose TSWN, middle dose TSWN and high dose TSWN by gavage for 12 weeks, respectively.ResultsMS and network pharmacology analyses suggested that TSWN might prevent DN through the sirtuin (SIRT)1/hypoxia-inducible factor (HIF)-1α pathway. Diabetic mice showed elevated urinary albumin in comparison with non-diabetic mice, and TSWN decreased urinary albumin in diabetic mice. Histological injury increased in the kidney in diabetic mice, which could be improved by TSWN. Fibrosis and collagen I expression were induced in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney; TSWN alleviated these effects. Apoptosis and cleaved caspase-3 were induced in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney, and TSWN blunted these effects. Podocytes were damaged in the diabetic mouse kidney, which was improved by TSWN. Podocin and nephrin amounts were decreased in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney, and podocalyxin was increased in urine of diabetic animals in comparison with non-diabetic counterparts. After TSWN treatment, podocin and nephrin were raised in the diabetic mouse kidney, and urinary podocalyxin was depressed in diabetic animals. Diabetic mice had lower SIRT1 and higher HIF-1α amounts in kidney specimens in comparison with non-diabetic mice, and TSWN promoted SIRT1 and inhibited HIF-1α in the diabetic mouse kidney. Moreover, co-staining of SIRT1 and podocin revealed that SIRT1 decreased in podocytes from diabetic mice in comparison with those from non-diabetic mice, and TSWN elevated SIRT1 in podocytes.ConclusionsThis study indicated that TSWN alleviates DN by improving podocyte injury through the SIRT1/HIF-1α pathway in diabetic mouse kidneys.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

TangShenWeiNing Formula Prevents Diabetic Nephropathy by Protecting Podocytes Through the SIRT1/HIF-1α Pathway

et al. 2022

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“…Hypoxia can also lead to podocyte injury by overexpressing hypoxia inducible factor-1 (HIF1). Podocytes can present with podocyte epithelial-mesenchymal transition (EMT), slit-diaphragm dysfunction, foot process effacement, and cytoskeletal derangement due to accumulation of HIF1, which contributed to pathology of glomerular diseases and proteinuria ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Arterial-Arteriolar Sclerosis Is Independently Associated With Poor Renal Outcome in IgA Nephropathy Patients

Dong

Tan

et al. 2021

Front. Med.

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Aim: This study aimed to investigate the clinicopathological features and prognosis of immunoglobulin A nephropathy (IgAN) with arterial-arteriolar sclerosis (AS).Methods: Patients with biopsy-proven IgAN from the West China Hospital of Sichuan University were retrospectively enrolled. Clinicopathological features were collected. Patients were categorized based on the presence and the severity of the AS. All the patients were regularly followed-up until a composite end point. The correlation between AS and prognosis of IgAN was assessed.Results: A total of 1,424 patients were recruited and followed for 60.0 ± 28.7 months. Patients with AS tended to have older age, higher blood pressure, heavier proteinuria, higher serum creatinine, uric acid, and total triglyceride (TG). Meanwhile, they were more likely to have a lower estimated glomerular filtration rate (eGFR), hemoglobin, and albumin. At the end of follow-up, 126 patients in the AS group and 47 patients in the non-AS group had reached the composite end point (p < 0.001). AS was associated with the renal outcome (log-rank p < 0.001) and was an independent risk factor for the progression of IgAN (p = 0.049). The severity of AS was associated with renal outcomes (log-rank p < 0.001) and there was a trend that it might serve as an independent risk marker for progression of IgAN. In the subgroup analysis, patients presenting with AS and lower eGFR, albumin, and hemoglobin or higher proteinuria, uric acid, and TG had a significant trend for a shorter time to reach the end point (log-rank p < 0.001).Conclusion: AS was commonly seen in patients with IgAN and was independently associated with the poor prognosis.

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“…According to the difference of α subunit, it can be divided into three subtypes: HIF-1, HIF-2 and HIF-3 [3]. And HIF-1 is the central molecule in the oxygen sensitive mechanism [13]. In contrast to HIF-1β, the expression and activity of hypoxia-inducible factor-1 alpha (HIF-1α) are regulated by oxygen levels [14].…”

Section: Introductionmentioning

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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Detrimental effects of hypoxia on glomerular podocytes

Cited by 18 publications

References 87 publications

TangShenWeiNing Formula Prevents Diabetic Nephropathy by Protecting Podocytes Through the SIRT1/HIF-1α Pathway

TangShenWeiNing Formula Prevents Diabetic Nephropathy by Protecting Podocytes Through the SIRT1/HIF-1α Pathway

Arterial-Arteriolar Sclerosis Is Independently Associated With Poor Renal Outcome in IgA Nephropathy Patients

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

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