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.
Bibliographical noteFunding Information:
The TEM technical service was supported by the George O’Brien Kidney Translational Core Center at the University of Michigan (DK081943). This research was supported by grants from the National Institutes of Health (NIH) to W.Z. (DK091405, DK081943 sub) and F.H. (DK076683, DK086542) and the Janette Ferrantino Investigator Award (W.Z.) and the American Society of Nephrology Carl W. Gottschalk Scholar Research Grant (W.Z.). The TALEN assembly was supported by the NIH grant to Dr. Keith Joung (GM088040). Z.C. is supported by the National Natural Science Foundation of China (No. 81100490, No. 81470943). H.Y.G. is supported by the American Society of Nephrology-Nephcure Foundation for Kidney Research Grant. F.H. is an investigator of the Howard Hughes Medical Institute and was supported by the Neph-Cure Foundation.
Copyright © 2016 by the American Society of Nephrology.
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