Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1.
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.
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
Xiaoyang
X
Wan
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; Jinling Hospital, Nanjing, China;
Zhaohong
Z
Chen
Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; and.
Won-Il
WI
Choi
Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; and.
Heon Yung
HY
Gee
Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; and Howard Hughes Medical Institute, Chevy Chase, Maryland.
Friedhelm
F
Hildebrandt
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; weibinz@med.umich.edu.
Weibin
W
Zhou
D000818:Animals; D051242:Caveolin 1 / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D009404:Nephrotic Syndrome / Q000209:etiology; D050199:Podocytes / Q000502:physiology*; D015854:Up-Regulation; D015027:Zebrafish
D051242:Caveolin 1; C486403:EMP2 protein, human; D008562:Membrane Glycoproteins
nephrotic syndrome; podocyte; proteinuria; zebrafish