Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Doi, Kent; Okamoto, Koji; Negishi, Kousuke; Suzuki, Yoshiyuki; Nakao, Akihide; Fujita, Toshiro; Toda, Akiko; Yokomizo, Takehiko; Kita, Yoshiaki; Kihara, Yasuyuki; Ishii, Satoshi; Shimizu, Takao; Noiri, Eisei

doi:10.2353/ajpath.2006.050634

Cited by 72 publications

(62 citation statements)

References 57 publications

(55 reference statements)

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“…28 HIF-2␣ expression induced in the FA kidney on day 7 suggested the presence of tissue hypoxia. HO-1, an acute stress marker, is known to be a microsomal enzyme that catalyzes the oxidation of heme to the antioxidant molecules, biliverdin and carbon monoxide.…”

Section: Discussionmentioning

confidence: 99%

Urinary Excretion of Liver Type Fatty Acid Binding Protein Accurately Reflects the Degree of Tubulointerstitial Damage

Yokoyama

Kamijo‐Ikemori

Sugaya

et al. 2009

The American Journal of Pathology

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To investigate the relationship between liver-type fatty acid-binding protein (L-FABP), a biomarker of chronic kidney disease, in the kidney and the degree of tubulointerstitial damage, folic acid (FA)-induced nephropathy was studied in a mouse model system. As renal L-FABP is not expressed in wild-type mice, human L-FABP (hL-FABP) transgenic mice were used in this study. hL-FABP is expressed in the renal proximal tubules of the transgenic mice that were injected intraperitoneally with FA in NaHCO 3 (the FA group) or only NaHCO 3 (the control group) and oral saline solution daily during the experimental period. The FA group developed severe tubulointerstitial damage with the infiltration of macrophages and the deposition of type I collagen on days 3 and 7 and recovered to the control level on day 14. The gene and protein expression levels of hL-FABP in the kidney were significantly enhanced on days 3 and 7. Urinary hL-FABP in the FA group was elevated on days 3 and 7 and decreased to the control level on day 14. The protein expression levels of hL-FABP in both the kidney and urine significantly correlated with the degree of tubulointerstitial damage, the infiltration of macrophages, and the deposition of type I collagen. In conclusion, renal expression and urinary excretion of hL-FABP significantly reflected the severity of tubulointerstitial damage in FA-induced nephropathy.

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Section: Discussionmentioning

confidence: 99%

Urinary Excretion of Liver Type Fatty Acid Binding Protein Accurately Reflects the Degree of Tubulointerstitial Damage

Yokoyama

Kamijo‐Ikemori

Sugaya

et al. 2009

The American Journal of Pathology

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“…Male C57BL/6 mice (aged 8-10 weeks) were given a single intraperitoneal injection of 250 mg/kg FA dissolved in 250 mM sodium bicarbonate or saline control based on previous literature (Doi et al, 2006). Mice were injected with sildenafil (0.3 mg/kg) or diluent every 24 hours beginning 1 day after FA injection.…”

Section: Methodsmentioning

confidence: 99%

cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

Whitaker

Wills

Stallons

et al. 2013

J Pharmacol Exp Ther

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Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours. PDE3, but not PDE4, inhibitors increased the FCCP-uncoupled oxygen consumption rate (OCR), a marker of MB. Exposure of RPTCs to the PDE3 inhibitors, cilostamide and trequinsin, for 24 hours increased peroxisome proliferator-activated receptor g coactivator-1a, and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mitochondrial DNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, whereas 8-Br-cAMP had no effect. The cGMPspecific PDE5 inhibitor sildenafil also induced MB in RPTCs and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid-induced AKI promoted restoration of MB and renal recovery. These data provide strong evidence that specific PDE inhibitors that increase cGMP are inducers of MB in vitro and in vivo, and suggest their potential efficacy in AKI and other diseases characterized by mitochondrial dysfunction and suppressed MB.

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“…41 After centrifugation of the samples, the supernatants were used as heart whole tissue lysates. The lysates were boiled in sample buffer containing 5% SDS with 20% 2-mercaptoethanol and were separated on a 10%-15% SDS-PAGE.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…34,41 Quantification of gene expressions was calculated relative to b-actin. Amplification data were analyzed using software (Prism Sequence Detection System version 2.1; Applied Biosystems, Foster City, CA).…”

Section: Real-time Pcr Assay For Tnf-a Expression In the Heartmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

Sumida¹,

Doi²,

Ogasawara³

et al. 2015

Journal of the American Society of Nephrology

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Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.

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Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Cited by 72 publications

References 57 publications

Urinary Excretion of Liver Type Fatty Acid Binding Protein Accurately Reflects the Degree of Tubulointerstitial Damage

Urinary Excretion of Liver Type Fatty Acid Binding Protein Accurately Reflects the Degree of Tubulointerstitial Damage

cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

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