Chronic Hypoxia and Tubulointerstitial Injury

Nangaku, Masaomi

doi:10.1681/asn.2005070757

Cited by 1,021 publications

(918 citation statements)

References 76 publications

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“…In addition, oxidative stress likely mediates many of the deleterious effects of I/R injury, 36,37 with the tubulointerstitium as the main target. 38,39 Recent studies suggest that Cygb may sense oxygen concentration and act as a regulatory protein that protects cells from ROS. 9 Therefore, it was hypothesized that up-regulation of Cygb protein may have a protective role against oxidative stress in the hypoxic kidney.…”

Section: Discussionmentioning

confidence: 99%

Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

Nishi

Inagi

Kawada

et al. 2011

The American Journal of Pathology

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Section: Discussionmentioning

confidence: 99%

Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

Nishi

Inagi

Kawada

et al. 2011

The American Journal of Pathology

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“…30,31 Hypoxia of tubular and interstitial cells leads to apoptosis or epithelial-mesenchymal transdifferentiation resulting in interstitial fibrosis. As a result of fibrosis, oxygen diffusion from peritubular capillaries to tubular and interstitial cells decreases, and finally, a vicious cycle is formed.…”

Section: Discussionmentioning

confidence: 99%

“…32 Renal insufficiency with almost normal urinalysis can be a clinical manifestation of absent or mild glomerular changes with severe tubulointerstitial injury and renal arterio-arteriolosclerosis. 30 Recently, it has been noted that a substantial proportion of type 2 diabetes mellitus patients have renal insufficiency without albuminuria. 33,34 MacIsaac et al 34 showed that in type 2 diabetes mellitus patients with renal insufficiency, intra-renal resistive index obtained by Doppler ultrasound, which reflects intra-renal vascular injury, 35 was high regardless of the amount of albuminuria.…”

Section: Discussionmentioning

confidence: 99%

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

et al. 2010

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Hypertension has an important function in the formation of renal arterio-arteriolosclerosis. However, renal arterioarteriolosclerosis is sometimes found in biopsy specimens of normotensive patients, which indicates unknown factors may contribute to renal arterio-arteriolosclerosis. In this study, we aimed to evaluate the effects of glucose metabolism/insulin resistance on renal arterio-arteriolosclerosis. Forty-eight patients with biopsy-proven non-diabetic chronic glomerular disease were included. Renal arterio-arteriolosclerosis was evaluated as the percentage of vessels showing hyaline changes or wall thickening. We correlated renal arterio-arteriolosclerosis with clinical parameters including indices obtained by 75 g oral glucose tolerance test. Of the 48 patients, 30 had hypertension. The results of univariate analysis showed significant association of renal arterio-arteriolosclerosis with hypertension, increased serum creatinine (S-Cr), hypertriglyceridemia, increased 2-h plasma glucose (PG) and increased 2-h plasma insulin (PI). In stepwise multiple regression analysis, hypertension (b¼0.344, P¼0.009), S-Cr (b¼0.287, P¼0.03) and 2-h PG (b¼0.274, P¼0.03) were independently associated with renal arterioarteriolosclerosis. Eleven of the 30 hypertensive patients did not have renal arterio-arteriolosclerosis. The hypertensive patients with renal arterio-arteriolosclerosis showed significantly higher 2-h PG (134 ± 25 vs. 106 ± 26 mg per 100 ml, P¼0.008) and higher 2-h PI (67.7 ± 34.9 vs. 48.3 ± 30.0 lU ml À1 , P¼0.04) compared with those without renal arterio-arteriolosclerosis, but the difference in S-Cr was not significant. Postprandial hyperglycemia and hyperinsulinemia may contribute to the formation of renal arterio-arteriolosclerosis independently of hypertension.

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“…Accumulating evidence emphasizes chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage kidney injury [29,30].…”

Section: Chronic Kidney Diseasementioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

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Chronic Hypoxia and Tubulointerstitial Injury

Cited by 1,021 publications

References 76 publications

Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

Hypoxia and the HIF system in kidney disease

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