Abstract
BackgroundThe glomerular podocyte is a highly specialized cell type with the ability to ultrafilter blood and support glomerular capillary pressure. However, little is known about the genetic programs leading to this functionality or the final phenotype.ResultsIn the current study, we found that the expression of a myocardin/MKL family member, MKL1, was significantly upregulated during cell cycle arrest induced by a temperature switch in murine podocyte clone 5 (MPC5) cells. Further investigation demonstrated that overexpression of MKL1 led to inhibition of cell proliferation by decreasing the number of cells in S phase of the cell cycle. In contrast, MKL1 knockdown by RNA interference had the opposite effect, highlighting a potential role of MKL1 in blocking G1/S transition of the cell cycle in MPC5 cells. Additionally, using an RT2 Profiler PCR Array, p21 was identified as a direct target of MKL1. We further revealed that MKL1 activated p21 transcription by recruitment to the CArG element in its promoter, thus resulting in cell cycle arrest. In addition, the expression of MKL1 is positively correlated with that of p21 in podocytes in postnatal mouse kidney and significantly upregulated during the morphological switch of podocytes from proliferation to differentiation.ConclusionsOur observations demonstrate that MKL1 has physiological roles in the maturation and development of podocytes, and thus its misregulation might lead to glomerular and renal dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12867-015-0029-5) contains supplementary material, which is available to authorized users.
Highlights
The glomerular podocyte is a highly specialized cell type with the ability to ultrafilter blood and support glomerular capillary pressure
We found that Megakaryoblastic leukemia 1 (MKL1) expression was upregulated during temperature-switched growth arrest in murine podocyte clone 5 (MPC5) cells
Expression of MKL1 is upregulated during temperature-switched cell growth arrest in MPC5 cells To assess the possible role of myocardin/MKL proteins in podocyte growth arrest, MPC5 cells were respectively maintained at the permissive temperature of 33°C and at the nonpermissive temperature of 37°C for 10 days
Summary
The glomerular podocyte is a highly specialized cell type with the ability to ultrafilter blood and support glomerular capillary pressure. Called visceral glomerular epithelial cells, are terminally differentiated cells overlaying the outer region of the glomerular basement membrane of renal glomeruli. These cells have several key functions including the prevention of proteinuria, synthesis of basement membrane components, regulation of glomerular filtration, and counteraction of intraglomerular hydrostatic pressure [1]. Podocytes are derived from epithelial cells originating in the metanephric mesenchyme, which develop into postmitotic terminally differentiated cells, and have similarities to neurons [3,4]. MKL1 has been recently shown to be a member of a three-protein family that includes MKL2 and myocardin These myocardin/MKL proteins serve as serum response factor (SRF) coactivators by binding to SRF and
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