Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model

Ohtomo, Shuichi; Nangaku, Masaomi; Izuhara, Yuko; Takizawa, Shunya; Strihou, Charles van Ypersele de; Miyata, Toshio

doi:10.1093/ndt/gfm715

Cited by 123 publications

(118 citation statements)

References 31 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…25 The finding that chronic HIF activation reduced proteinuria is in line with previous studies. Song et al 26 recently showed that HIF activation halted progression of proteinuria in a 27 reported that HIF activation by cobalt reduced renal expressions of TGF-b, connective tissue growth factor, and NADPH oxidase as well as reduced proteinuria, tubulointerstitial damage, and peritubular capillary loss in experimental type 2 diabetes. Indeed, tubulointerstitial fibrosis is a reliable marker for progression of kidney disease, and it is, therefore, interesting that HIF activation ameliorated fibrosis development in the diabetic kidney.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

176

145

View full text Add to dashboard Cite

Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetesinduced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Animals were The control and STZ-injected animals were randomly divided into receiving either vehicle or CoCl 2 (20 mgzkg body wt 21 per 24 hours 21 ) in the drinking water for the entire duration of diabetes. 27 A detailed schematic drawing of the experimental design is depicted in Figure 9.…”

Section: Animals Induction Of Diabetes and Chronic Treatmentmentioning

confidence: 99%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

176

145

View full text Add to dashboard Cite

show abstract

“…This is of significant clinical relevance. Because cobalt has been under development as a drug to promote HIF-1 transcriptional activity (Endoh et al, 2000;Ohtomo et al, 2008), factors affecting its efficacy and long-term safety have to be considered. It is reasonable to consider the use of cobalt to promote angiogenesis in ischemic tissues.…”

Section: Downloaded Frommentioning

confidence: 99%

“…The mechanism of action of cobalt involves the inhibition of prolyl hydroxylases (Yuan et al, 2003;Maxwell and Salnikow, 2004;Hirsila et al, 2005;Ke et al, 2005). Because of the pivotal role of HIF-1 in multiple cellular function and homeostasis, cobalt has been extensively studied for its potential as a drug to stimulate cellular function regulated by HIF-1 (Endoh et al, 2000;Ohtomo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Copper Is Required for Cobalt-Induced Transcriptional Activity of Hypoxia-Inducible Factor-1

Qiu

Ding²,

Zhang³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Cobalt inhibits prolyl hydroxylases, leading to the accumulation of hypoxia-inducible factor-1␣ (HIF-1␣) and a concomitant increase in the transcriptional activity of HIF-1. Therefore, cobalt has been under development as a drug for activating HIF-1 under some disease conditions. However, it has been shown that ischemic conditions resulted in the loss of copper, and the activation of HIF-1 would not occur unless copper was supplemented. The present study was undertaken to test the hypothesis that copper is also required for the cobalt activation of HIF-1 transcriptional activity. Human umbilical vein endothelial cells subjected to treatment with cobalt chloride (CoCl 2 ) at concentrations above 25 M for 2 h resulted in an accumulation of HIF-1␣, which was determined by Western blot analysis, and an increase in the expression of vascular endothelial growth factor (VEGF), which was determined by real-time reverse transcription-polymerase chain reaction analysis for mRNA levels and enzyme-linked immunosorbent assay analysis for protein levels. The copper chelator tetraethylenepentamine at 25 M did not significantly affect the accumulation of HIF-1␣ but blocked increases in VEGF mRNA and protein levels, an effect that could be reversed by the addition of 25 M copper sulfate (CuSO 4 ). In addition, gene silencing of the copper chaperone for Cu,Zn-superoxide dismutase blocked VEGF expression with little effect on cobalt-induced HIF-1␣ accumulation. The present study thus demonstrates that copper was required for cobalt-activated transcriptional activity of HIF-1, although copper did not affect cobalt-induced accumulation of HIF-1␣ in the cells.

show abstract

“…Induction of HIF-1␣ by CoCl 2 ameliorates the renal injury in rats with nephritis (60) and hypertensive type 2 diabetes (46). In contrast to the deleterious effects of overexpressed HIF-1␣ in 5 ⁄6 nephrectomy mice (23), other reports have shown that upregulation of HIF-1␣ by pharmacological agents protects the kidneys using the same 5 ⁄6 nephrectomy model of CKD (6,56,59).…”

mentioning

confidence: 98%

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

View full text Add to dashboard Cite

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...

show abstract

Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model

Abstract: Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.

Cited by 123 publications

References 31 publications

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Copper Is Required for Cobalt-Induced Transcriptional Activity of Hypoxia-Inducible Factor-1

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

Contact Info

Product

Resources

About