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      Role of Parietal Epithelial Cells in Kidney Injury: The Case of Rapidly Progressing Glomerulonephritis and Focal and Segmental Glomerulosclerosis


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          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.

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          Most cited references24

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          NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.

          Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.
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            Progression of glomerular diseases: is the podocyte the culprit?

            The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of "bare" GBM. which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architectural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis.
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              Recruitment of podocytes from glomerular parietal epithelial cells.

              Loss of a critical number of podocytes from the glomerular tuft leads to glomerulosclerosis. Even in health, some podocytes are lost into the urine. Because podocytes themselves cannot regenerate, we postulated that glomerular parietal epithelial cells (PECs), which proliferate throughout life and adjoin podocytes, may migrate to the glomerular tuft and differentiate into podocytes. Here, we describe transitional cells at the glomerular vascular stalk that exhibit features of both PECs and podocytes. Metabolic labeling in juvenile rats suggested that PECs migrate to become podocytes. To prove this, we generated triple-transgenic mice that allowed specific and irreversible labeling of PECs upon administration of doxycycline. PECs were followed in juvenile mice beginning from either postnatal day 5 or after nephrogenesis had ceased at postnatal day 10. In both cases, the number of genetically labeled cells increased over time. All genetically labeled cells coexpressed podocyte marker proteins. In conclusion, we demonstrate for the first time recruitment of podocytes from PECs in juvenile mice. Unraveling the mechanisms of PEC recruitment onto the glomerular tuft may lead to novel therapeutic approaches to renal injury.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                May 2014
                19 May 2014
                : 126
                : 2
                : 97-100
                Nephrology and Clinical Immunology, Medizinische Klinik II, University Hospital of the RWTH Aachen University, Aachen, Germany
                Author notes
                *Marcus J. Moeller, Medizinische Klinik II, University Hospital of the RWTH Aachen University, Pauwelsstrasse 30, DE-52074 Aachen (Germany), E-Mail mmoeller@ukaachen.de
                360677 Nephron Exp Nephrol 2014;126:97-100
                © 2014 S. Karger AG, Basel

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                Page count
                Pages: 4
                Further Section

                Cardiovascular Medicine,Nephrology
                Glomerulosclerosis,Crescent,Glomerulonephritis,Parietal epithelial cell,Podocyte


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