PARIETAL EPITHELIAL CELLS
Biology of glomerular parietal epithelial cells (PECs)
The study and understanding of PECs has lacked significantly compared to other kidney cells, such that their functions and roles in the pathobiology of glomerular diseases have only been delineated in the past 5+ years, and as a community, we likely have only scratched the surface.
We have made several important contributions to the field to date.
1) We showed that by expressing several tight junction proteins, PECs serve an important role in limiting the passage of protein from
the urinary space to the extraglomerular space (a). Indeed, when tight junctions are disrupted in disease, albumin and other proteins
escape into the extra- glomerular space, where they contribute to the peri-glomerular inflammation and fibrosis that characterized
progressive proteinuric glomerular diseases.
(a) Ohse T, Chang AM, Pippin JW, Jarad G, Hudkins KL, Alpers CE, Miner JH, Shankland SJ.
A new function for parietal epithelial cells: a second glomerular barrier.
Am J Physiol Renal. 2009;297(6):F1566-74. PMID 19794110. PMCID: 2801333.
2) We developed the first immortalized mouse PEC line for study in cell culture (b). These cells are now widely used by numerous
groups internationally, from which many publications have arisen.
(b) Ohse T, Pippin JW, Vaughan MR, Brinkkoetter PT, Shankland SJ.
Establishment of conditionally immortalized mouse glomerular parietal epithelial cells in culture.
J Am Soc Nephrol. 2008;19(10):1879-90. PMID: 18596122. PMCID: 2551564
3) We have several publications showing that the expression profile, and likely biological functions of PECs, changes in settings where
podocytes are the primary target of disease (c1). Our data shows that in states of podocyte depletion, PECs lining Bowman’s capsule
begin to co-express several proteins considered specific for podocytes. A subset of PECs co-expressing podocyte proteins migrate to
the glomerular tuft, suggesting that they may serve as adult podocyte progenitors.
We have also published three additional manuscripts showing that when mice are given either dexamethasone, ACE-inhibitors or
retinoids, that the improvement in podocyte number coincides with an increase in the subset of PECs expressing podocyte proteins.
These studies strongly suggest an adult podocyte progenitor function for PECs in states of podocyte depletion. In a mouse model of
focal segmental glomerulosclerosis typified by abrupt podocyte depletion followed by regeneration, PECs can participate in either a
pro-fibrotic or regenerative pathway once they migrate to the glomerular tuft. An initial pro-fibrotic response is predominated by
activated PECs that are CD44+ and phospho-ERK+, while a later regenerative response is typified by CD44+ phosphor-ERK- progenitor
cells that co-express podocyte proteins (c2).
(c1) Zhang J, Pippin JW, Krofft RD, Naito S, Liu ZH, Shankland SJ.
Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS.
Am J Physiol Renal2013;304(11):F1375-89. PMID: 23486009. PMCID: 3680690.
(c2) Eng DG, Sunseri MW, Kaverina NV, Roeder SS, Pippin JW, Shankland SJ.
Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental
Kidney Int. 2015 Nov;88(5):999-1012. PMID: 25993321. PMCID: 4654724.
4) The exact genetic makeup of PECs is not known, and the field needs to better understand what genes are constitutively expressed
by PECs. We have reported on the transcriptional landscape for PECs, and how this profile differs from neighboring podocytes (d).
These studies have already benefited the community, as many are using this dataset for further studies.
(d) Gharib SA, Pippin JW, Ohse T, Pickering SG, Krofft RD, Shankland SJ.
Transcriptional landscape of glomerular parietal epithelial cells.
PLoS One. 2014 Aug 15;9(8) PMID: 25127402. PMCID: 4134297.
How PECs might contribute to glomerular disease
When PECs or APEMPs are activated or dysregulated, identified by de novo CD44 expression, they can either lead to glomerulosclerosis by
migrating and producing ECM proteins unique to the parietal basement membrane (also called Bowman’s capsule) or undergoing
proliferation leading to crescent and/or pseudocrescent formation. Proliferation of a subset of dysregulated PECs expressing CD133 and
CD24, so called APEMPs, might also contribute to crescent and/or pseudocrescent formation. This pathway is dependent on intracellular
retinoic acid, levels of which can be decreased (represented by dashed line) by albumin endocytosis by PECs. The latter has additional
consequences, including apoptosis, a reduction in the levels of tight junction proteins or both, leading to increased albumin permeability
beyond the PEC–parietal basement membrane barrier, and to peri-glomerular inflammation. The consequences of EMT are not yet
understood. Abbreviations: APEMP, adult parietal epithelial multipotent progenitor; ECM, extracellular matrix; EMT, epithelial–
mesenchymal transformation; glycCD133, glycosylated CD133; PEC, parietal epithelial cell.