Efficacy of Darbepoetin in Doxorubicin-Induced Cardiorenal Injury in Rats

Noiri, Eisei; Nagano, Nobuo; Negishi, Kousuke; Doi, Kent; Miyata, Sonoe; Abe, Masataka; Tanaka, Tamami; Okamoto, Koji; Hanafusa, Norio; Kondo, Yasushi; Ishizaka, Nobukazu; Fujita, Toshiro

doi:10.1159/000093258

Cited by 20 publications

(20 citation statements)

References 41 publications

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“…For example, in CKD due to unilateral ureteral obstruction (UUO) in rats, rhEPO delivered daily after induction of UUO reduced the profibrotic growth factor trans-forming growth factor-␤ (TGF-␤) and decreased fibrosis and epithelial-to-mesenchymal transition (EMT) (45,60). Similar results have been published in the 5 ⁄6 nephrectomy CKD model (4,61,62) and in nephrotoxic animal models of CKD (33,43). In the brain, EPO protected neurons after hypoxic injury but also stimulated growth of glial cells (69) and fibroblasts (53).…”

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confidence: 58%

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Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Gobé

Bennett

West

et al. 2014

American Journal of Physiology-Renal Physiology

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Treatment of renal ischemia-reperfusion (IR) injury with recombinant human erythropoietin (rhEPO) reduces acute kidney injury and improves function. We aimed to investigate whether progression to chronic kidney disease associated with acute injury was also reduced by rhEPO treatment, using in vivo and in vitro models. Rats were subjected to bilateral 40-min renal ischemia, and kidneys were studied at 4, 7, and 28 days postreperfusion for renal function, tubular injury and repair, inflammation, and fibrosis. Acute injury was modulated using rhEPO (1,000 or 5,000 IU/kg, intraperitoneally) at the time of reperfusion. Renal tubular epithelial cells or fibroblasts in culture were subjected to hypoxia or oxidative stress, with or without rhEPO (200 IU/ml), and fibrogenesis was studied. The results of the in vivo model confirmed functional and structural improvement with rhEPO at 4 days post-IR ( P < 0.05). At 7 days post-IR, fibrosis and myofibroblast stimulation were increased with IR with and without rhEPO ( P < 0.01). However, at 28 days post-IR, renal fibrosis and myofibroblast numbers were significantly greater with IR plus rhEPO ( P < 0.01) compared with IR only. Mechanistically, rhEPO stimulated profibrotic transforming growth factor-β, oxidative stress (marker 8-hydroxy-deoxyguanosine), and phosphorylation of the signal transduction protein extracellular signal-regulated kinase. In vitro, rhEPO protected tubular epithelium from apoptosis but stimulated epithelial-to-mesenchymal transition and also protected and activated fibroblasts, particularly with oxidative stress. In summary, although rhEPO was protective of renal function and structure in acute kidney injury, the supraphysiological dose needed for renoprotection contributed to fibrogenesis and stimulated chronic kidney disease in the long term.

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confidence: 58%

“…These CKD models differ greatly in mechanism, if not outcome, from our model of IR-induced AKI followed by CKD. The closest model to our IR-AKI model is one where there was a reduction in tubulointerstitial fibrosis after doxorubicin nephrotoxicity in rats (43). Darbepoetin was delivered once weekly 2 wk after the last dose of doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Gobé

Bennett

West

et al. 2014

American Journal of Physiology-Renal Physiology

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“…The Sprague-Dawley rats were randomly divided into (1) a DXR nephropathy group and (2) a vehicle group. The DXR nephropathy model was produced using a previously reported procedure [12]. Under anesthesia, 3 mg/kg of DXR was initially injected into the tail vein first and 2 weeks later, another 2 mg/kg of DXR was injected.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we hypothesized that EPO may regulate Klotho expression. In a previous study, darbepoetin α reduced doxorubicin hydrochloride (DXR)-induced renal injury [12]; however, the efficacy of rhEPO in rats with DXR-induced nephropathy remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Human Erythropoietin Mitigates Reductions in Renal Klotho Expression

Sugiura¹,

Yoshida²,

Mitobe³

et al. 2010

Am J Nephrol

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Background: Erythropoietin (EPO) and Klotho expression have both been detected in the kidney. Since a recent study suggested that both EPO and Klotho mitigate kidney damage, we explored the relation between EPO and Klotho in a doxorubicin hydrochloride (DXR)-induced rat nephropathy model treated with recombinant human erythropoietin (rhEPO). Methods: Male Sprague-Dawley rats were subjected to DXR-induced nephropathy. The rhEPO group was intracutaneously injected with rhEPO twice weekly at 4–16 weeks after the DXR injection. The rats were sacrificed at 16 weeks after the DXR administration. Expression of renal Klotho, HSP70, α-smooth-muscle actin and E-cadherin were assessed using real-time PCR or western blotting. The hematocrit, plasma creatinine and phosphate levels were also determined. Immunohistochemical studies and Masson-trichrome staining were performed. Results: The renal Klotho mRNA and Klotho protein expressions were significantly reduced in the DXR nephropathy group. Treatment with rhEPO improved the serum creatinine, phosphate level and histological changes observed in the DXR nephropathy group. The reduction in Klotho expression induced by DXR nephropathy was mitigated by rhEPO administration. Conclusion: rhEPO is involved in the pathophysiology of DXR nephropathy. rhEPO mitigated elevated plasma phosphate concentrations in an experimental model of chronic kidney disease via the expression of Klotho.

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“…The area of interstitial fibrosis in the cortex was evaluated using the computer-aided evaluation program AIS (Fuji Photo Film, Tokyo), as described previously [14]. Viewed at ×200, ten randomly selected nonoverlapping fields ranging from the outer medulla to the cortical region were analyzed.…”

Section: Methodsmentioning

confidence: 99%

Urinary Human L-FABP Is a Potential Biomarker to Predict COX-Inhibitor-Induced Renal Injury

Tanaka

Noiri²,

Yamamoto³

et al. 2008

Nephron Exp Nephrol

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Background/Aim: A strong demand exists for the development of sensitive biomarkers in the nephrology field. We propose urinary human L-type fatty acid binding protein (L-FABP) as an earlier biomarker to detect the outcome of chronic renal injury induced by cyclooxygenase (COX) inhibitors using human L-FABP transgenic mice. Methods: After consuming a low-sodium diet for 2 weeks, transgenic mice were administered meloxicam or celecoxib with the low-sodium diet. Mice were sacrificed 2 days and 4 weeks after starting COX inhibitors, and urine was collected 24 and 48 h and 1, 2, 3, and 4 weeks after starting COX inhibitors. Celecoxib-treated mice were divided into responders or nonresponders according to urinary L-FABP levels, and histology, urinary L-FABP and peritubular capillary blood flow were evaluated. Results: Meloxicam-treated mice showed a higher blood pressure than control mice. Urinary L-FABP was significantly increased in COX inhibitor-treated mice. Peritubular capillary blood flow in all meloxicam-treated mice and in some celecoxib-treated mice was significantly decreased. Although blood urea nitrogen was not increased, interstitial fibrosis and macrophage infiltration were revealed, especially in meloxicam-treated mice. Responders showed an increase of fibrotic areas and correlations between urinary L-FABP and peritubular capillary blood flow. Conclusion: Urinary L-FABP is capable of revealing chronic renal injury induced by COX inhibitors.

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Efficacy of Darbepoetin in Doxorubicin-Induced Cardiorenal Injury in Rats

Cited by 20 publications

References 41 publications

Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Recombinant Human Erythropoietin Mitigates Reductions in Renal Klotho Expression

Urinary Human L-FABP Is a Potential Biomarker to Predict COX-Inhibitor-Induced Renal Injury

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