대한신장학회

논문분류	춘계학술대회 초록집
제목	PGC-1α Protects Against Notch1-Induced Kidney Injury
저자	Meiyan Wu* 1, Bo Young Nam1, Jung Tak Park2, Tae-Hyun Yoo2, Shin-Wook Kang1, 2, Seung Hyeok Han2
출판정보	2016; 2016(1):
키워드	Fibrosis, Notch, Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha
초록	Background: Notch signaling has been highlighted as a major contributor to the development of kidney fibrosis. We recently found that fatty acid oxidation is down-regulated in human chronic kidney disease (CKD) and various kidney fibrosis models. PGC-1α is known as a key regulator of energy metabolism and mitochondrial biogenesis. However, there is lacking of evidence on whether PGC-1α provides a protective effect against kidney damage. Therefore, this study aimed to identify the effect of PGC-1α on kidney fibrosis using mice with tubule-specific double overexpression of Notch1 and PGC-1α. Methods: Using human kidney samples, we analyzed expression pattern of PGC-1α in human CKD. For animal study, we crossed mice expressing Pax8-rtTA/tetO-ICN1 with mice harboring Pax8-rtTA/tetO-Ppargc1a to create Pax8-rtTA/tetO-ICN1/tetO-Ppargc1a mice. The littermate tetO-ICN1 or tetO-Ppargc1a mice (without Pax8-rtTA) were considered controls. Using kidney tissues from these mice, we examined fatty acid oxidation pathway and cell death. To delineate relationship between Notch1 and PGC-1α, chromatin immunoprecipitation (ChIP) assay was performed. Results: Microarray analysis revealed PPARGC1A transcript level positively correlated with estimated glomerular filtration rate. Immunohistochemistry further confirmed that protein expression of PGC-1α was significantly decreased in advanced stages of CKD. Compared to control and Pax8-rtTA/tetO-Ppargc1a mice, normal renal architecture was lost and animals developed severe tubular dilatation and fibrosis in Pax8-rtTA/tetO-ICN1 mice. In contrast, dilated tubules were significantly less and fibrosis was almost null in Pax8-rtTA/tetO-ICN1/tetO-Ppargc1a mice. In Notch1 overexpressing mice, transcript and protein expression levels of fatty acid oxidation were significantly decreased compared to control mice. The decreases in expression of these genes were significantly restored by PGC-1α overexpression. In addition, PGC-1α overexpression attenuated the increased apoptosis rate in mice with Notch1 overexpression. Finally, ChIP assay revealed that the transcriptional repressor Hes1, a downstream target of Notch1 signaling, can directly regulate PGC-1α in kidney tubular epithelial cells (TECs). Conclusion: This study showed that PGC-1α is directly regulated by Notch signaling. The reduced PGC-1α activity by Notch overexpression resulted in kidney fibrosis through impaired fatty acid oxidation and genetic delivery of PGC-1α in renal TECs almost nullified Notch-induced kidney fibrosis. Our findings suggest that PGC-1α can provide a protective effect against kidney injury and restoring its activity can be a promising therapeutic strategy in the management of CKD.
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