Impact of Cyclin B2 and Cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats

Nishihara, Kumiko; Masuda, Satohiro; Nakagawa, Shoichi; Yonezawa, Atsushi; Ichimura, Takaharu; Bonventre, Joseph V.; Inui, Ken Ichi

doi:10.1152/ajprenal.00567.2009

Cited by 12 publications

(17 citation statements)

References 45 publications

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“…PTC injury is characterized by release of enzymes such as KIM-1, a marker of brush border injury [30,31,] and neprilysin (e.g. neutral endopeptidase 24.11), an enzyme localized to the brush border and responsible for degrading Ang II [32].…”

Section: Resultsmentioning

confidence: 99%

Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin

Whaley‐Connell

Habibi

Panfili³

et al. 2011

Am J Nephrol

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Background/Aims: Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis. Methods: We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT₁R) blocker telmisartan (2 mg · kg^–1 · day^–1) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function. Results: Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine²⁴⁴⁸ phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats. Conclusions: Our observations suggest that Ang II activation of the AT₁R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.

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Section: Resultsmentioning

confidence: 99%

Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin

Whaley‐Connell

Habibi

Panfili³

et al. 2011

Am J Nephrol

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“…Rats treated with the same volume of saline were used as Sham-treated rats. For the chronic renal failure model, cisplatin (2 mg/kg) or saline (vehicle) was administered on the 14th day after subtotal nephrectomy [8], and urine and blood samples were collected on days 1, 2, 4, and 7 after the administration of cisplatin or vehicle. Rats were maintained in metabolic cages for 24 h to determine urinary output levels and creatinine clearance.…”

Section: Methodsmentioning

confidence: 99%

Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity

Nishihara¹,

Masuda²,

Shinke³

et al. 2013

Biochemical Pharmacology

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Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5 mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2 mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury.

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“…Based on the gene-expressional analysis with the in silico mRNA expressional database for the Nx rat kidney, we successfully cloned novel genes, such as Na + /<small cap>D</small cap>-glucose cotransporter NaGLT1 and riboflavin transporters RFT1 and RFT3 (Horiba et al, 2003;Yonezawa et al, 2008;Yao et al, 2010). Further, using microarray analysis with the isolated proximal tubules, time-dependent expressional changes in tubular transporters were clarified in rats after Nx (Nishihara et al, 2010). Administration of the mTOR inhibitor, sirolimus, increased expression levels of the decreased tubular transporters in uremic rats, and the urinary excretion of albumin was correspondingly decreased (Nakagawa et al, 2010).…”

Section: Department Of Pharmacy Kyoto University Hospital Kyoto Japanmentioning

confidence: 99%

Invited Speaker Abstracts

2011

Drug Metabolism Reviews

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The liver and kidney, the major clearance organs in the human body, express drug transporters, which are involved in uptake and subsequent efflux processes. Their transport activities are critical factors for the systemic exposure and elimination pathways of their substrate drugs. Overall, hepatobiliary transport of organic anions consists of three processes: sinusoidal uptake, sinusoidal efflux, and canalicular efflux. Pharmacokinetic analysis, using blood concentration-time profile, provides only intrinsic clearance for overall transport. In contrast, by determining concentration-time profile of drugs in the liver, intrinsic clearances for each process can be evaluated separately. This is particularly important for the investigation of rate-determining process, drug-drug interaction mechanisms, and determination of the in vitro/in vivo scaling factor for each process in humans. Further, time profiles of drugs in the brain provide the uptake and efflux clearances of drugs in the brain, which contribute to the deep understanding in the transport mechanisms of drugs across the human blood-brain barrier (BBB). Imaging technologies, such as single-photon emission computed tomography Invited Speaker AbstractsDrug Metabolism Reviews, 2011; 43(S1): 2-21 (SPECT) and positron emission tomography (PET), enable the evaluation of time profile of the tissue concentration in a noninvasive manner, using radiolabeled ligands with short half-lives. Such technologies have been used for the diagnosis of tissue function, neurodegenerative illnesses, and tumor. Particularly, the high sensitivity and exceptional spatial-temporal resolution of PET make it an extremely useful tool for estimating the in vivo function of drug transporters in various tissues over time after intravenous administration of a radiolabeled drug. Recently, there is growing interest in the use of these imaging technologies for pharmacokinetic analysis of drug disposition in humans. Several SPECT and PET probes for drug transporters have been developed and applied to pharmacokinetic analysis of hepatobiliary transport and BBB transport in humans. This symposium will illustrate the recent progress in molecular-imaging technologies and their application to the quantitative transporter research in humans.Although considerable evidence is available from rodents (e.g., mdr1a/b(-/-) mice) that P-glycoprotein (P-gp) is important at the blood-brain barrier (BBB) in excluding drugs from the brain, the pharmacological and physiological importance of this transporter at the human BBB has not been quantified. For example, recent evidence suggests that P-gp may be important in the removal of beta-amyloid from the brain, a factor that is important in causing Alzheimer's disease. Thus, this raises the following question: Is P-gp activity at the BBB compromised in Alzheimer's disease? Moreover, if P-gp at the human BBB is as important as that in rodents in excluding drugs from the brain, then the potential for clinically significant drug interactions is high. Such interactions c...

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Impact of Cyclin B2 and Cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats

Cited by 12 publications

References 45 publications

Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin

Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin

Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity

Invited Speaker Abstracts

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