Silencing of Hypoxia-Inducible Factor-1α Gene Attenuated Angiotensin II–Induced Renal Injury in Sprague-Dawley Rats

Zhu, Qing; Wang, Zhengchao; Xia, Min; Li, Pin‐Lan; Tassell, Benjamín W. Van; Abbate, Antonio; Dhaduk, Romesh; Li, Ningjun

doi:10.1161/hypertensionaha.111.177626

Cited by 75 publications

(68 citation statements)

References 68 publications

(89 reference statements)

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“…Specifically, the oxygen tension of the kidney cortex and medulla has been shown to be approximately 10 mm Hg lower than normal in spontaneously hypertensive rats and other models of hypertension as well as in hypertensive patients. 15,89,[144][145][146] The role of hypertension in the progression of CKD was first described in 1914 by Volhard and Fahr. 13 Subsequently, it was appreciated that hypertension predisposes to kidney failure by inducing renal hypoxia.…”

Section: Hypertensionmentioning

confidence: 99%

Hypoxia: The Force that Drives Chronic Kidney Disease

Colgan

Shelley

2016

Clinical Medicine & Research

120

104

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In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy.

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Section: Hypertensionmentioning

confidence: 99%

Hypoxia: The Force that Drives Chronic Kidney Disease

Colgan

Shelley

2016

Clinical Medicine & Research

120

104

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“…We have also reported that silencing HIF-1␣ gene expression attenuates angiotensin II-induced profibrotic effects and transforming growth factor (TGF) ␤1-induced EMT in renal cells in vitro and in vivo (13,62,71). A more recent study has shown that increasing HIF-1␣ level exacerbates the kidney damage in a rat model of hypertension induced by a high-salt diet and nitric oxide withdrawal (5).…”

mentioning

confidence: 99%

Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats

Wang

Zhu

et al. 2014

American Journal of Physiology-Renal Physiology

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Silencing of hypoxia-inducible factor-1␣ gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol 306: F1236 -F1242, 2014. First published March 12, 2014 doi:10.1152/ajprenal.00673.2013.-Overactivation of hypoxia-inducible factor (HIF)-1␣ is implicated as a pathogenic factor in chronic kidney diseases (CKD). However, controversy exists regarding the roles of HIF-1␣ in CKD. Additionally, although hypoxia and HIF-1␣ activation are observed in various CKD and HIF-1␣ has been shown to stimulate fibrogenic factors, there is no direct evidence whether HIF-1␣ is an injurious or protective factor in chronic renal hypoxic injury. The present study determined whether knocking down the HIF-1␣ gene can attenuate or exaggerate kidney damage using a chronic renal ischemic model. Chronic renal ischemia was induced by unilaterally clamping the left renal artery for 3 wk in Sprague-Dawley rats. HIF-1␣ short hairpin (sh) RNA or control vectors were transfected into the left kidneys. Experimental groups were shamϩcontrol vector, clipϩcontrol vector, and clipϩHIF-1␣ shRNA. Enalapril was used to normalize blood pressure 1 wk after clamping the renal artery. HIF-1␣ protein levels were remarkably increased in clipped kidneys, and this increase was blocked by shRNA. Morphological examination showed that HIF-1␣ shRNA significantly attenuated injury in clipped kidneys: glomerular injury indices were 0.71 Ϯ 0.04, 2.50 Ϯ 0.12, and 1.34 Ϯ 0.11, and the percentage of globally damaged glomeruli was 0.02, 34.3 Ϯ 5.0, and 6.3 Ϯ 1.6 in sham, clip, and clipϩshRNA groups, respectively. The protein levels of collagen and ␣-smooth muscle actin also dramatically increased in clipped kidneys, but this effect was blocked by HIF-1␣ shRNA. In conclusion, long-term overactivation of HIF-1␣ is a pathogenic factor in chronic renal injury associated with ischemia/hypoxia. collagen; ␣-smooth muscle actin; renal fibrosis; chronic kidney diseases REDUCED RENAL TISSUE OXYGEN levels have been demonstrated in a large variety of chronic kidney diseases (CKD) in both human patients and in experimental animal models. Hypoxia in CKD results from a combination of structural and functional changes (12, 36). As a result, hypoxia-inducible factor (HIF)-1␣ has been reported to be consistently upregulated in almost all types of CKD (7, 16, 17, 36 -38). However, it is unclear whether upregulation of HIF-1␣ is beneficial or deleterious in progressive CKD. HIF-1␣ is a transcription factor and has been shown to stimulate collagen accumulation (7,15,43,44) and promote the epithelial-to-mesenchymal transition (EMT) (11,35), an important mechanism involved in the progression of CKD (3,33,57,67). Therefore, although upregulation of HIF-1␣ is protective in acute kidney injury (9, 18, 37, 53), ample evidence indicates that long-term overactivation of HIF-1␣ may be a pathogenic factor in CKD (10,16,21,24,36,45).Previous studies have shown that genetic ablation of renal epithelial HIF-1␣ inhibits the development of renal tubulointerstitia...

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“…Previous studies have shown that HIF-1α activation is a risk factor for kidney disease (10,26,27) and that activated HIF-1α may transcribe some pro-apoptotic genes, such as BNIP3 and NIX, or stabilize p53, leading to apoptosis. We explored how the HIF-1α and apoptosis pathways are altered by miR-210 overexpression or knockdown, since miR-210 targeted 3′UTR of HIF-1α mRNA directly.…”

Section: Mir-210 Attenuated Hypoxic Apoptosis By Suppressing Hif-1` Amentioning

confidence: 99%

“…In contrast, miR-210 inhibitor exerts adverse effects on hypoxic HK-2 cells. Many studies have shown that HIF-1α activation is a risk factor for cell survival in hypoxia (44,45) and that HIF-1α inhibition may be used as a therapeutic strategy for treating kidney damage (10). Previous studies revealed that activated HIF-1α can damage cells by inducing BNIP3 and NIX (46)(47)(48) or by stabilizing the tumor suppressor p53 (14).…”

Section: Mir-210 Alleviated Hypoxia-induced Cell Injury and Apoptosismentioning

confidence: 99%

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miR-210 Protects Renal Cell Against Hypoxia-induced Apoptosis by Targeting HIF-1 Alpha

Liu

Li²,

He³

et al. 2017

Mol Med

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The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1-α (HIF-1α) activation. ) is known to be induced by HIF-1α and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, especially in renal tubular cells. A similar increase was observed in hypoxia-treated human renal tubular HK-2 cells. We also verified that miR-210 can directly suppress HIF-1α expression by targeting the 3′ untranslated region of HIF-1α mRNA in HK-2 cells in severe hypoxia. Accordingly, miR-210 overexpression caused significant inhibition of the HIF-1α pathway and attenuated apoptosis caused by hypoxia, while miR-210 knockdown exerted the opposite effect. Taken together, our findings verify that miR-210 is involved in the molecular response in hypoxic kidney lesions in vivo and attenuates hypoxia-induced renal tubular cell apoptosis by targeting HIF-1α directly and suppressing HIF-1α pathway activation in vitro.

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Silencing of Hypoxia-Inducible Factor-1α Gene Attenuated Angiotensin II–Induced Renal Injury in Sprague-Dawley Rats

Cited by 75 publications

References 68 publications

Hypoxia: The Force that Drives Chronic Kidney Disease

Hypoxia: The Force that Drives Chronic Kidney Disease

Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats

miR-210 Protects Renal Cell Against Hypoxia-induced Apoptosis by Targeting HIF-1 Alpha

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