Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

Kyoung Hye Kong, Hyung Jung Oh, Beom Jin Lim, Minsuk Kim, Ki Hwan Han, Youn Hee Choi, Kihwan Kwon, Bo Young Nam, Kyoung Sook Park, Jung Tak Park, Seung Hyeok Han, Tae Hyun Yoo, Shina Lee, Seung Jung Kim, Duk Hee Kang, Kyu Bok Choi, Vera Eremina, Susan E. Quaggin, Dong Ryeol Ryu, Shin Wook Kang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.

Original languageEnglish
Article number11351
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

Fingerprint

Fibrosis
Kidney
Chronic Renal Insufficiency
Collagen Type I
Fibronectins
Vascular Endothelial Growth Factor A
endothelial PAS domain-containing protein 1
Hypoxia-Inducible Factor 1
Cell Hypoxia
p38 Mitogen-Activated Protein Kinases
Transgenic Mice
Protein Isoforms
Hypoxia
Messenger RNA
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Kong, Kyoung Hye ; Oh, Hyung Jung ; Lim, Beom Jin ; Kim, Minsuk ; Han, Ki Hwan ; Choi, Youn Hee ; Kwon, Kihwan ; Nam, Bo Young ; Park, Kyoung Sook ; Park, Jung Tak ; Han, Seung Hyeok ; Yoo, Tae Hyun ; Lee, Shina ; Kim, Seung Jung ; Kang, Duk Hee ; Choi, Kyu Bok ; Eremina, Vera ; Quaggin, Susan E. ; Ryu, Dong Ryeol ; Kang, Shin Wook. / Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis. In: Scientific reports. 2017 ; Vol. 7, No. 1.
@article{ae07ae9fe55d4a16a5cbc92ea6adac0e,
title = "Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis",
abstract = "Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.",
author = "Kong, {Kyoung Hye} and Oh, {Hyung Jung} and Lim, {Beom Jin} and Minsuk Kim and Han, {Ki Hwan} and Choi, {Youn Hee} and Kihwan Kwon and Nam, {Bo Young} and Park, {Kyoung Sook} and Park, {Jung Tak} and Han, {Seung Hyeok} and Yoo, {Tae Hyun} and Shina Lee and Kim, {Seung Jung} and Kang, {Duk Hee} and Choi, {Kyu Bok} and Vera Eremina and Quaggin, {Susan E.} and Ryu, {Dong Ryeol} and Kang, {Shin Wook}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-11829-2",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

Kong, KH, Oh, HJ, Lim, BJ, Kim, M, Han, KH, Choi, YH, Kwon, K, Nam, BY, Park, KS, Park, JT, Han, SH, Yoo, TH, Lee, S, Kim, SJ, Kang, DH, Choi, KB, Eremina, V, Quaggin, SE, Ryu, DR & Kang, SW 2017, 'Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis', Scientific reports, vol. 7, no. 1, 11351. https://doi.org/10.1038/s41598-017-11829-2

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis. / Kong, Kyoung Hye; Oh, Hyung Jung; Lim, Beom Jin; Kim, Minsuk; Han, Ki Hwan; Choi, Youn Hee; Kwon, Kihwan; Nam, Bo Young; Park, Kyoung Sook; Park, Jung Tak; Han, Seung Hyeok; Yoo, Tae Hyun; Lee, Shina; Kim, Seung Jung; Kang, Duk Hee; Choi, Kyu Bok; Eremina, Vera; Quaggin, Susan E.; Ryu, Dong Ryeol; Kang, Shin Wook.

In: Scientific reports, Vol. 7, No. 1, 11351, 01.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

AU - Kong, Kyoung Hye

AU - Oh, Hyung Jung

AU - Lim, Beom Jin

AU - Kim, Minsuk

AU - Han, Ki Hwan

AU - Choi, Youn Hee

AU - Kwon, Kihwan

AU - Nam, Bo Young

AU - Park, Kyoung Sook

AU - Park, Jung Tak

AU - Han, Seung Hyeok

AU - Yoo, Tae Hyun

AU - Lee, Shina

AU - Kim, Seung Jung

AU - Kang, Duk Hee

AU - Choi, Kyu Bok

AU - Eremina, Vera

AU - Quaggin, Susan E.

AU - Ryu, Dong Ryeol

AU - Kang, Shin Wook

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.

AB - Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.

UR - http://www.scopus.com/inward/record.url?scp=85029322079&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029322079&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-11829-2

DO - 10.1038/s41598-017-11829-2

M3 - Article

C2 - 28900259

AN - SCOPUS:85029322079

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 11351

ER -