Background: Millions of people are affected by irreversible loss of renal function and thus by a significantly increased cardiovascular risk. In this context, the parietal epithelial cells (PECs) of the glomerulus have attracted increasing attention in recent years. So far, they have been ascribed 2 major functions: (1) PECs may act as intrinsic progenitor cells to replenish podocytes and/or proximal tubular cells and (2) a major role of PECs has been proposed in 2 glomerular disease entities [i.e. rapidly progressing glomerulonephritis (RPGN) and focal and segmental glomerulosclerosis (FSGS)]. Summary: In this review, the major recent findings regarding the role of PECs in glomerular disease are summarized. Novel transgenic technologies have allowed major advances, in particular cell fate-tracing studies. Key Messages: Using these methods, it could be established that the proliferating cells in Bowman's space, which are characteristically found in RPGN, are derived almost exclusively from the glomerular epithelium - primarily PECs. Similarly, it could be shown that PECs participate in the formation of sclerotic lesions in FSGS. Since PECs deposit their characteristic extracellular matrix within these lesions, they likely contribute to the sclerotic process. A common feature of both diseases is that PECs are ‘activated', i.e. PECs acquire a larger cytoplasm and nucleus and show increased migration and/or proliferation. Activated PECs can be identified by de novo expression of the marker CD44. These findings broaden our understanding of the pathogenesis of 2 different glomerular diseases: RPGN and FSGS. The participation of activated PECs in both diseases identifies these cells as prime pharmacological targets to develop more specific therapies for both diseases.

1.
Smeets B, Uhlig S, Fuss A, Mooren F, Wetzels JF, Floege J, Moeller MJ: Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells. J Am Soc Nephrol 2009;20:2604-2615.
[PubMed]
2.
Rizzo P, Perico N, Gagliardini E, Novelli R, Alison MR, Remuzzi G, Benigni A: Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat. Am J Pathol 2013;183:1769-1778.
[PubMed]
3.
Zhang J, Pippin JW, Krofft RD, Naito S, Liu Z, Shankland SJ: Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS. Am J Physiol Renal Physiol 2013;304:F1375-F1389.
[PubMed]
4.
Le Hir M, Besse-Eschmann V: A novel mechanism of nephron loss in a murine model of crescentic glomerulonephritis. Kidney Int 2003;63:591-599.
[PubMed]
5.
Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ: Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 2009;20:333-343.
[PubMed]
6.
Moeller MJ, Soofi A, Hartmann I, Le Hir M, Wiggins R, Kriz W, Holzman LB: Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J Am Soc Nephrol 2004;15:61-67.
[PubMed]
7.
Thorner PS, Ho M, Eremina V, Sado Y, Quaggin S: Podocytes contribute to the formation of glomerular crescents. J Am Soc Nephrol 2008;19:495-502.
[PubMed]
8.
Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C, Mazzinghi B, Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J, Romagnani P: Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 2009;20:2593-2603.
[PubMed]
9.
Sicking EM, Fuss A, Uhlig S, Jirak P, Dijkman H, Wetzels J, Engel DR, Urzynicok T, Heidenreich S, Kriz W, Kurts C, Ostendorf T, Floege J, Smeets B, Moeller MJ: Subtotal ablation of parietal epithelial cells induces crescent formation. J Am Soc Nephrol 2012;23:629-640.
[PubMed]
10.
Macary G, Rossert J, Bruneval P, Mandet C, Belair MF, Houillier P, Duong Van Huyen JP: Transgenic mice expressing nitroreductase gene under the control of the podocin promoter: a new murine model of inductible glomerular injury. Virchows Arch 2009;456:325-337.
[PubMed]
11.
Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, Hashizume H, Wang QC, Pastan I, Fogo AB, Ichikawa I: Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury. J Am Soc Nephrol 2005;16:1013-1023.
[PubMed]
12.
Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC: Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 2005;16:2941-2952.
[PubMed]
13.
Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPSH2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000;24:349-354.
[PubMed]
14.
Buscher AK, Konrad M, Nagel M, Witzke O, Kribben A, Hoyer PF, Weber S: Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. Clin Nephrol 2012;78:47-53.
[PubMed]
15.
Kriz W, Gretz N, Lemley KV: Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 1998;54:687-697.
[PubMed]
16.
Van Damme B, Tardanico R, Vanrenterghem Y, Desmet V: Adhesions, focal sclerosis, protein crescents, and capsular lesions in membranous nephropathy. J Pathol 1990;161:47-56.
[PubMed]
17.
Dijkman H, Smeets B, van der Laak J, Steenbergen E, Wetzels J: The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis. Kidney Int 2005;68:1562-1572.
[PubMed]
18.
Smeets B, Kuppe C, Sicking EM, Fuss A, Jirak P, van Kuppevelt TH, Endlich K, Wetzels JF, Grone HJ, Floege J, Moeller MJ: Parietal epithelial cells participate in the formation of sclerotic lesions in focal segmental glomerulosclerosis. J Am Soc Nephrol 2011;22:1262-1274.
[PubMed]
19.
Fatima H, Moeller MJ, Smeets B, Yang HC, D'Agati VD, Alpers CE, Fogo AB: Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant. Clin J Am Soc Nephrol 2012;7:1852-1858.
[PubMed]
20.
Smeets B, Moeller MJ: Parietal epithelial cells and podocytes in glomerular diseases. Semin Nephrol 2012;32:357-367.
[PubMed]
21.
Wijnhoven TJ, Lensen JF, Rops AL, van der Vlag J, Kolset SO, Bangstad HJ, Pfeffer P, van den Hoven MJ, Berden JH, van den Heuvel LP, van Kuppevelt TH: Aberrant heparan sulfate profile in the human diabetic kidney offers new clues for therapeutic glycomimetics. Am J Kidney Dis 2006;48:250-261.
[PubMed]
22.
Berger K, Schulte K, Boor P, Kuppe C, van Kuppelvelt TH, Floege J, Smeets B, Moeller MJ: The regenerative potential of parietal epithelial cells in adult mice. J Am Soc Nephrol 2014, E-pub ahead of print.
[PubMed]
23.
Sakamoto K, Ueno T, Kobayashi N, Hara S, Takashima Y, Pastan I, Matsusaka T, Nagata M: The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis. Am J Physiol Renal Physiol 2014;306:F98-F104.
[PubMed]
24.
Guhr SS, Sachs M, Wegner A, Becker JU, Meyer TN, Kietzmann L, Schlossarek S, Carrier L, Braig M, Jat PS, Stahl RA, Meyer-Schwesinger C: The expression of podocyte-specific proteins in parietal epithelial cells is regulated by protein degradation. Kidney Int 2013;84:532-544.
[PubMed]
25.
Moeller MJ, Smeets B: Novel target in the treatment of RPGN: the activated parietal cell. Nephrol Dial Transplant 2013;28:489-492.
[PubMed]
You do not currently have access to this content.