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

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 <i>in vivo</i> 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 <i>Srf</i> gene was conditionally inactivated with <i>NPHS2</i>-<i>Cre</i> 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 <i>Srf</i>-null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.