Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Bing Guo, Qing Lyu, Orazio J. Slivano, Ronald Dirkx, Christine K. Christie, Jan Czyzyk, Aram F. Hezel, Ali G. Gharavi, Eric M. Small, Joseph M. Miano

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the in vivo expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the Srf gene was conditionally inactivated with NPHS2-Cre exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the Srf-null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.

Original languageEnglish (US)
Pages (from-to)416-422
Number of pages7
JournalJournal of the American Society of Nephrology
Volume29
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

Bibliographical note

Funding Information:
B.G. is supported by a grant from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. A.G.G. is supported by Department of Defense Peer Reviewed Medical Investigator-Initiated Research award PR151419, and E.M.S. is supported by National Institutes of Health (NIH) grants HL120919 and HL133761. J.M.M. is supported by NIH grants HL112793 and HL117907.

Funding Information:
We thank Karen L. De Mesy Bentley and the University of Rochester Medical Center Electron Microscopy Core for generating the electron microscopic images. B.G. is supported by a grant from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. A.G.G. is supported by Department of Defense Peer Reviewed Medical Investigator-Initiated Research award PR151419, and E.M.S. is supported by National Institutes of Health (NIH) grants HL120919 and HL133761. J.M.M. is supported by NIH grants HL112793 and HL117907.

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