Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling

Masanori Kugita, Kazuhiro Nishii, Miwa Morita, Daisuke Yoshihara, Hiroe Kowa-Sugiyama, Koji Yamada, Tamio Yamaguchi, Darren P. Wallace, James P. Calvet, Hiroki Kurahashi, Shizuko Nagao

Research output: Contribution to journalArticle

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Abstract

Han: SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated "Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation," "LPS/IL-1-Mediated Inhibition of RXR Function," and "Liver X Receptor (LXR)/RXR Activation." These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number1
DOIs
Publication statusPublished - 01-01-2011

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Retinoid X Receptors
Polycystic Kidney Diseases
Gene Expression Profiling
Kidney
Cell Proliferation
Proliferating Cell Nuclear Antigen
Morphogenesis
Real-Time Polymerase Chain Reaction
Gene Ontology
Calcitriol Receptors
Missense Mutation
Microarray Analysis
Interleukin-1
Genes
Cysts
Cytoplasm
Up-Regulation
Epithelial Cells
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Kugita, Masanori ; Nishii, Kazuhiro ; Morita, Miwa ; Yoshihara, Daisuke ; Kowa-Sugiyama, Hiroe ; Yamada, Koji ; Yamaguchi, Tamio ; Wallace, Darren P. ; Calvet, James P. ; Kurahashi, Hiroki ; Nagao, Shizuko. / Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling. In: American Journal of Physiology - Renal Physiology. 2011 ; Vol. 300, No. 1.
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Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling. / Kugita, Masanori; Nishii, Kazuhiro; Morita, Miwa; Yoshihara, Daisuke; Kowa-Sugiyama, Hiroe; Yamada, Koji; Yamaguchi, Tamio; Wallace, Darren P.; Calvet, James P.; Kurahashi, Hiroki; Nagao, Shizuko.

In: American Journal of Physiology - Renal Physiology, Vol. 300, No. 1, 01.01.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling

AU - Kugita, Masanori

AU - Nishii, Kazuhiro

AU - Morita, Miwa

AU - Yoshihara, Daisuke

AU - Kowa-Sugiyama, Hiroe

AU - Yamada, Koji

AU - Yamaguchi, Tamio

AU - Wallace, Darren P.

AU - Calvet, James P.

AU - Kurahashi, Hiroki

AU - Nagao, Shizuko

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N2 - Han: SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated "Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation," "LPS/IL-1-Mediated Inhibition of RXR Function," and "Liver X Receptor (LXR)/RXR Activation." These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat.

AB - Han: SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated "Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation," "LPS/IL-1-Mediated Inhibition of RXR Function," and "Liver X Receptor (LXR)/RXR Activation." These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat.

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