Deficiency of hypoxia inducible factor‑1α promoted progression of diabetic nephropathy with hypertension

Jiao, Yuejiang; Jiang, Hongwei; Lu, Haibo; Yang, Yi‐Ping; Zhang, Yanfang; Zhang, Kun; Liu, Hui

doi:10.3892/etm.2018.6621

Cited by 16 publications

(18 citation statements)

References 26 publications

(35 reference statements)

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“…Furthermore, gut microbiota has been shown to play a role in the regulation blood pressure (Li et al, 2017;Marques et al, 2017;Ma and Li, 2018;Toral et al, 2019). Although Lassila et al did not observe differences in systolic blood pressure in the setting of diabetes as in the current study, this effect has been observed by others (Zhong et al, 2015;Jiao et al, 2018).…”

Section: Discussioncontrasting

confidence: 57%

Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease

et al. 2020

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It is well established that diabetes is the major cause of chronic kidney disease worldwide. Both hyperglycemia, and more recently, advanced glycation endproducts, have been shown to play critical roles in the development of kidney disease. Moreover, the renin-angiotensin system along with growth factors and cytokines have also been shown to contribute to the onset and progression of diabetic kidney disease; however, the role of lipids in this context is poorly characterized. The current study aimed to compare the effect of 20 weeks of streptozotocin-induced diabetes or western diet feeding on kidney disease in two different mouse strains, C57BL/6 mice and hyperlipidemic apolipoprotein (apo) E knockout (KO) mice. Mice were fed a chow diet (control), a western diet (21% fat, 0.15% cholesterol) or were induced with streptozotocin-diabetes (55 mg/kg/day for 5 days) then fed a chow diet and followed for 20 weeks. The induction of diabetes was associated with a 3-fold elevation in glycated hemoglobin and an increase in kidney to body weight ratio regardless of strain (p < 0.0001). ApoE deficiency significantly increased plasma cholesterol and triglyceride levels and feeding of a western diet exacerbated these effects. Despite this, urinary albumin excretion (UAE) was elevated in diabetic mice to a similar extent in both strains (p < 0.0001) but no effect was seen with a western diet in either strain. Diabetes was also associated with extracellular matrix accumulation in both strains, and western diet feeding to a lesser extent in apoE KO mice. Consistent with this, an increase in renal mRNA expression of the fibrotic marker, fibronectin, was observed in diabetic C57BL/6 mice (p < 0.0001). In summary, these studies demonstrate disparate effects of diabetes and hyperlipidemia on kidney injury, with features of the diabetic milieu other than lipids suggested to play a more prominent role in driving renal pathology.

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Section: Discussioncontrasting

confidence: 57%

Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease

et al. 2020

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“…In addition, Epo and the activation of its receptor decrease albuminuria, mesangial expansion and renal fibrosis [ 55 , 56 , 57 ]. Other studies have shown that overexpression of HIF-1α in tubular epithelial cells contributes to the progression of renal fibrosis, and the inhibition of HIF-1α expression prevents the progression of renal fibrosis and attenuated DN progression [ 19 , 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Further, it has been hypothesized that OS modulates hypoxic factors. Hypoxia inducible factor-1α (HIF-1α) is the main regulator of cellular response to hypoxia modulating multiple cellular processes in the kidney [ 15 , 19 ]. Under hypoxic conditions, HIF-1α modulates apoptosis, autophagy, inflammation, and cell cycle arrest, among other cellular mechanisms that are involved in renal protection [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes

et al. 2020

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This study aimed to assess the impact of allicin on the course of diabetic nephropathy. Study groups included control, diabetes, and diabetes-treated rats. Allicin treatment (16 mg/kg day/p.o.) started after 1 month of diabetes onset and was administered for 30 days. In the diabetes group, the systolic blood pressure (SBP) increased, also, the oxidative stress and hypoxia in the kidney cortex were evidenced by alterations in the total antioxidant capacity as well as the expression of nuclear factor (erythroid-derived 2)-like 2/Kelch ECH associating protein 1 (Nrf2/Keap1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin (Epo) and its receptor (Epo-R). Moreover, diabetes increased nephrin, and kidney injury molecule-1 (KIM-1) expression that correlated with mesangial matrix, the fibrosis index and with the expression of connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA). The insulin levels and glucose transporter protein type-4 (GLUT4) expression were decreased; otherwise, insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) expression was increased. Allicin increased Nrf2 expression and decreased SBP, Keap1, HIF-1α, and VEGF expression. Concurrently, nephrin, KIM-1, the mesangial matrix, fibrosis index, and the fibrotic proteins were decreased. Additionally, allicin decreased hyperglycemia, improved insulin levels, and prevented changes in (GLUT4) and IRSs expression induced by diabetes. In conclusion, our results demonstrate that allicin has the potential to help in the treatment of diabetic nephropathy. The cellular mechanisms underlying its effects mainly rely on the regulation of antioxidant, antifibrotic, and antidiabetic mechanisms, which can contribute towards delay in the progression of renal disease.

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“…Alternatively, hypoxic tubular cells activate the adaptive process for the survival against tissue hypoxia. 15 Hypoxia-inducible factor−1alpha (HIF-1α) is a key protein that plays a major role in modulating the reaction of tissue to hypoxia, HIF-1 has a heterodimeric structure consists of oxygen-sensitive HIF-1alpha subunit bound to constitutively expressed Beta (β) subunit that subsequently activates the HIF-response element (HRE) pro-survival genes that enhance oxygen delivery in hypoxic organs such as brain, heart, liver and kidney, [15][16][17] but its function is depressed in diabetes. 18,19 Although studies have shown that overexpression of HIF-1α in tubular epithelial cells contributes to renal fibrosis, its inhibition prevented the progression of renal fibrosis and attenuated diabetic kidney disease.…”

Section: Introductionmentioning

confidence: 99%

<p>Empagliflozin Protects Against Proximal Renal Tubular Cell Injury Induced by High Glucose via Regulation of Hypoxia-Inducible Factor 1-Alpha</p>

Ndibalema¹,

Kabuye²,

Wen³

et al. 2020

DMSO

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Background: Evidence from both animal and human studies clearly supports the renal beneficial effects of empagliflozin (emp), a sodium glucose co-transporter 2 (SGLT2) inhibitor, but the mechanism in which it exerts its effect is not well understood. In this study, we investigated the capability of emp on reducing hyperglycemia-induced renal proximal tubular epithelial cells injury and we evaluated if the renoprotective effect of emp associates with hypoxia-inducible factor-1α (HIF-1α). Materials and Methods: Human kidney cell lines (HK-2 cells) were incubated in normoxia, high glucose with or without emp treatment for 72 hours to evaluate the induction of HIF-1α, glucose transporter-1, SGLT2, the fibrosis signal pathway and epithelial-mesenchymal transition (EMT) markers. Results: High glucose (HG) increased expression of Collagen IV, Fibronectin, transforming growth factor-beta1 (TGF-β1). However, emp treatment remarkably decreased expression of TGF-β1, accumulation of extracellular matrix proteins (Fibronectin, Collagen IV), as well as (phosphorylated-smad3) P-smad3. HG increased SGLT2 protein expression compared to normal glucose (NG) while emp significantly decreased SGLT2 expression. Furthermore, emp decreased high glucose-induced alpha-smooth muscle actin (α-SMA) expression and reversed epithelial marker (E-catherin) suppression induced by high glucose. In addition, emp treatment for 72 h increased expression of HIF-1α protein (95% CI: -0.5918 to -0.002338, at 100nM, P < 0.05, 95% CI -0.6631 to -0.07367 at 500nM, P < 0.05) in hyperglycemic normoxic HK-2 cells. Furthermore, we observed increased expression of GLUT-1 protein after emp treatment and remarkably decreased cell proliferation. Conclusion: Emp treatment protected proximal renal tubular cells injury induced by high glucose. Induction of HIF-1α expression by emp may play an essential role in the protection of high glucose-induced proximal renal tubular epithelial cells injury.

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Deficiency of hypoxia inducible factor‑1α promoted progression of diabetic nephropathy with hypertension

Cited by 16 publications

References 26 publications

Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease

Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease

Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes

<p>Empagliflozin Protects Against Proximal Renal Tubular Cell Injury Induced by High Glucose via Regulation of Hypoxia-Inducible Factor 1-Alpha</p>

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