Renal cellular hypoxia in adenine‐induced chronic kidney disease

Fong, Debra; Ullah, Mahbub; Lal, Jaswini G.; Abdelkader, Amany; Ow, Connie P. C.; Hilliard, Lucinda M; Ricardo, Sharon D.; Kelly, Darren J.; Evans, Roger G.

doi:10.1111/1440-1681.12621

Cited by 20 publications

(34 citation statements)

References 53 publications

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“…Our results showed that CR2* and MR2* levels are significantly elevated in patients with CKD compared with healthy controls, which support the theory that renal hypoxia exists in patients with CKD [17,18]. The presence of renal hypoxia in patients with CKD is attributed to renal fibrosis and vasoconstriction induced by a variety of risk factors [19].…”

Section: Discussionsupporting

confidence: 84%

Renal Hypoxia: An Important Prognostic Marker in Patients with Chronic Kidney Disease

et al. 2018

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Background: Blood oxygen level-dependent (BOLD)-MRI is a novel and noninvasive tool that can assess renal oxygenation. The R2* value is a parameter of tissue deoxyhemoglobin concentration detected by BOLD-MRI. The purpose of the current study was to determine the relationships between renal R2* values and clinical parameters and to determine whether renal R2* values were associated with the risk for progression of chronic kidney disease (CKD). Methods: Sixty patients with CKD were enrolled in this prospective observational study in China from March 2013 to August 2014. A region of interest-based BOLD-MRI was performed to obtain cortical and medullary R2* (CR2* and MR2*) values. Data on demographics and clinical characteristics were collected. The primary end point (CKD progression) was defined as an absolute 30% decline in the estimated glomerular filtration rates (eGFR; CKD-Epidemiology Collaboration equations) or initiation of dialysis during follow-up. Results: The CR2* and MR2* values in patients with CKD were significantly higher compared with those of healthy controls. The CR2* levels were positively associated with 24-h urinary protein excretion, blood urea nitrogen, creatinine, and uric acid but negatively associated with baseline eGFR, 24-h creatinine clearance, eGFR slope, serum albumin, and the use of angiotensin II type 1 receptor blockade. The CR2* levels had the highest areas under the curve during follow-up compared with the MR2* levels and medullary cortical ratios. The Kaplan-Meier survival analysis showed that patients with CKD in the lowest tertile of the CR2* levels had the best prognosis compared with the other 2 tertiles. Moreover, baseline eGFR and CR2* tertiles were associated with the progression of CKD in Cox proportional hazard regression models. Only CR2* tertiles correlated negatively with the eGFR slope. Conclusion: We have demonstrated that the clinical feasibility of BOLD-MRI to evaluate renal oxygenation and cortex hypoxia aggravates with the decline of renal function, and cortex hypoxia was a prognostic marker in the progression of CKD.

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Section: Discussionsupporting

confidence: 84%

Renal Hypoxia: An Important Prognostic Marker in Patients with Chronic Kidney Disease

et al. 2018

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“…This CKD model was verified by other investigators. Administration of 0.2% adenine diet increased BUN and serum creatinine levels, and induced renal fibrosis and tissue hypoxia 32 , 33 . However, it may not be the classic CKD model as 5/6 nephrectomized animal and we cannot totally exclude the chemical effect of adenine on our findings.…”

Section: Discussionmentioning

confidence: 99%

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

Kong

Lim

et al. 2017

Sci Rep

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Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.Regardless of the type of initial injury to the kidney, renal hypoxia is the common final pathway of renal fibrosis 1 , which is regarded a prime target for preventing the progression of chronic kidney disease (CKD) to end-stage renal disease.Hypoxia-inducible factor (HIF) is a key transcriptional factor in the regulation of the adaptive response to hypoxia. HIF is a heterodimeric complex that has three forms (HIF-1, HIF-2, and HIF-3), which differ in their α-subunit. If the α-subunit is not hydroxylated by prolyl hydroxylase under hypoxic conditions, it cannot be recognized by von Hippel-Lindau tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex that targets HIF-α for proteosomal degradation 2 . Then, α-subunit combines with a constitutively expressed β-subunit in the nucleus. Finally, HIF regulates the expression of salient target genes that are involved in numerous biological processes, including energy metabolism, angiogenesis, erythropoiesis, iron metabolism, cell proliferation, and apoptosis 2 . HIF activation ameliorates tissue hypoxia and eventually helps the hypoxic cells survive. Even though the effect of HIF activation in CKD has been widely evaluated, the results have been inconsistent. Reduced renal fibrosis by genetic ablation of tubular HIF-1 suggested a profibrotic role of HIF 3 , while contrary results demonstrated that an HIF stabilizer exerted a beneficial effect on renal fibrosis in an animal model of CKD 4 . Accumulating evidence suggests that HIFs exert beneficial effects in diabetic nephropathy. Activation of HIFs by cobalt chloride, a non-specific pan-HIF activator, attenuated diabetes-induced alteration in oxygen m...

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“…Decreases in body weight are known to occur upon pair feeding [6] or oral gavage administration [15] of adenine. In this study, UNx had no immediate impact on weight gain since the body weights of the AD-1K and AD-2K animals were similar during the first 17 days of AD feeding.…”

Section: Discussionmentioning

confidence: 99%

A Novel Model of Chronic Kidney Disease in Rats: Dietary Adenine in Combination with Unilateral Nephrectomy

et al. 2019

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Background: Adenine at 0.75% in the diet (AD) triggers renal impairment in rats. This model of kidney disease is largely reversible when AD feeding is stopped. Testing of novel drugs parallel to AD administration may result in unwanted interference. Objectives: We hypothesized that combining AD with unilateral nephrectomy (UNx) would result in progressive chronic kidney disease (CKD) even after cessation of AD. Methods: In an explorative study, 16 rats with UNx (AD-1K rats) and 10 sham-operated rats (AD-2K rats) received AD-supplemented feed for 3 weeks, followed by 4 weeks of standard chow. Ten sham-operated rats receiving only standard chow served as controls. Laboratory parameters in blood and urine were frequently assessed during and after cessation of AD feeding. Comprehensive pathological examinations were performed in all rats at the end of the experiment. Results: Rats with UNx were more affected by impaired glomerular filtration rate, anemia, hyperphosphatemia, and hypocalcemia. After cessation of AD feeding, recovery was poorest in AD-1K rats, paralleled by increased proteinuria indicative of progressive CKD. Scores in histopathological damage of the kidneys indicative of CKD were seen in both AD-fed groups, with key parameters being more affected in AD-1K rats. Histopathological changes in the heart were most prominent in AD-1K rats. Conclusions: Combining AD feeding with UNx provides a time window after cessation of AD feeding for the testing of drugs without interference. Our findings in rats may have implications for research in other target animal species as well.

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Renal cellular hypoxia in adenine‐induced chronic kidney disease

Cited by 20 publications

References 53 publications

Renal Hypoxia: An Important Prognostic Marker in Patients with Chronic Kidney Disease

Renal Hypoxia: An Important Prognostic Marker in Patients with Chronic Kidney Disease

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

A Novel Model of Chronic Kidney Disease in Rats: Dietary Adenine in Combination with Unilateral Nephrectomy

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