Loss of epithelial membrane protein 2 aggravates podocyte injury via upregulation of caveolin-1

Xiaoyang Wan, Zhaohong Chen, Won Il Choi, Heon Yung Gee, Friedhelm Hildebrandt, Weibin Zhou

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease–based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury.

Original languageEnglish
Pages (from-to)1066-1075
Number of pages10
JournalJournal of the American Society of Nephrology
Volume27
Issue number4
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

Caveolin 1
Podocytes
Membrane Proteins
Up-Regulation
Wounds and Injuries
Zebrafish
Glucocorticoids
Nephrotic Syndrome
Phenotype
Glomerular Filtration Barrier
Puromycin Aminonucleoside
Caveolae
Hypoalbuminemia
Hyperlipidemias
Proteinuria
Edema
Embryonic Structures
Kidney
Mutation

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Wan, Xiaoyang ; Chen, Zhaohong ; Choi, Won Il ; Gee, Heon Yung ; Hildebrandt, Friedhelm ; Zhou, Weibin. / Loss of epithelial membrane protein 2 aggravates podocyte injury via upregulation of caveolin-1. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 4. pp. 1066-1075.
@article{e3368ac44ef244e1a7b3ec5cc5b253d6,
title = "Loss of epithelial membrane protein 2 aggravates podocyte injury via upregulation of caveolin-1",
abstract = "Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease–based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury.",
author = "Xiaoyang Wan and Zhaohong Chen and Choi, {Won Il} and Gee, {Heon Yung} and Friedhelm Hildebrandt and Weibin Zhou",
year = "2016",
month = "1",
day = "1",
doi = "10.1681/ASN.2014121197",
language = "English",
volume = "27",
pages = "1066--1075",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "4",

}

Loss of epithelial membrane protein 2 aggravates podocyte injury via upregulation of caveolin-1. / Wan, Xiaoyang; Chen, Zhaohong; Choi, Won Il; Gee, Heon Yung; Hildebrandt, Friedhelm; Zhou, Weibin.

In: Journal of the American Society of Nephrology, Vol. 27, No. 4, 01.01.2016, p. 1066-1075.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of epithelial membrane protein 2 aggravates podocyte injury via upregulation of caveolin-1

AU - Wan, Xiaoyang

AU - Chen, Zhaohong

AU - Choi, Won Il

AU - Gee, Heon Yung

AU - Hildebrandt, Friedhelm

AU - Zhou, Weibin

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease–based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury.

AB - Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease–based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury.

UR - http://www.scopus.com/inward/record.url?scp=85017049440&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017049440&partnerID=8YFLogxK

U2 - 10.1681/ASN.2014121197

DO - 10.1681/ASN.2014121197

M3 - Article

C2 - 26264854

AN - SCOPUS:85017049440

VL - 27

SP - 1066

EP - 1075

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 4

ER -