The recruitment mechanisms and potential therapeutic targets of podocytes from parietal epithelial cells

AbstractPodocytes are differentiated postmitotic cells which cannot be replaced after podocyte injury. The mechanism of podocyte repopulation after injury has aroused wide concern. Parietal epithelial cells (PECs) are heterogeneous and only a specific subpopulation of PECs has the capacity to replace podocytes. Major progress has been achieved in recent years regarding the role and function of a subset of PECs which could transdifferentiate toward podocytes. Additionally, several factors, such as Notch, Wnt/ß-catenin, Wilms’ tumor-1, miR-193a and growth arrest-specific protein 1, have been shown to be involved in these processes. Finally, PECs serve as a potential therapeutic target in the conditions of podocyte loss. In this review, we discuss the latest observations and concepts about the recruitment of podocytes from PECs in glomerular diseases as well as newly identified mechanisms and the most recent treatments for this process.

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Cre recombinase toxicity in podocytes: a novel genetic model for FSGS in adolescent mice

AJP Renal Physiology ◽

10.1152/ajprenal.00573.2018 ◽

2019 ◽

Vol 317 (5) ◽

pp. F1375-F1382 ◽

Cited By ~ 1

Author(s):

Madeleine Frahsek ◽

Kevin Schulte ◽

Arnaldo Chia-Gil ◽

Sonja Djudjaj ◽

Herdit Schueler ◽

...

Keyword(s):

Epithelial Cells ◽

Focal Segmental Glomerulosclerosis ◽

Genetic Model ◽

Transgenic Animals ◽

Cre Recombinase ◽

Young Age ◽

Podocyte Injury ◽

Sclerotic Lesions ◽

Parietal Epithelial Cells ◽

Time Point

Here, we show that inducible overexpression of Cre recombinase in glomerular podocytes but not in parietal epithelial cells may trigger focal segmental glomerulosclerosis (FSGS) in juvenile transgenic homocygous Pod-rtTA/LC1 mice. Administration of doxycycline shortly after birth, but not at any other time point later in life, resulted in podocyte injury and development of classical FSGS lesions in these mice. Sclerotic lesions were formed as soon as 3 wk of age, and FSGS progressed with low variability until 13 wk of age. In addition, our experiments identified Cre toxicity as a potentially relevant limitation for studies in podocytes of transgenic animals. In summary, our study establishes a novel genetic model for FSGS in mice, which exhibits low variability and manifests already at a young age.

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Podocyte Injury in Lupus Nephritis

Journal of Clinical Medicine ◽

10.3390/jcm8091340 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1340 ◽

Cited By ~ 3

Author(s):

Hamza Sakhi ◽

Anissa Moktefi ◽

Khedidja Bouachi ◽

Vincent Audard ◽

Carole Hénique ◽

...

Keyword(s):

Epithelial Cells ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Glomerular Injury ◽

Crescent Formation ◽

Podocyte Injury ◽

Inflammatory Processes ◽

Lupus Podocytopathy ◽

Parietal Epithelial Cells ◽

Lupus Glomerulonephritis

Systemic lupus erythematosus (SLE) is characterized by a broad spectrum of renal lesions. In lupus glomerulonephritis, histological classifications are based on immune-complex (IC) deposits and hypercellularity lesions (mesangial and/or endocapillary) in the glomeruli. However, there is compelling evidence to suggest that glomerular epithelial cells, and podocytes in particular, are also involved in glomerular injury in patients with SLE. Podocytes now appear to be not only subject to collateral damage due to glomerular capillary lesions secondary to IC and inflammatory processes, but they are also a potential direct target in lupus nephritis. Improvements in our understanding of podocyte injury could improve the classification of lupus glomerulonephritis. Indeed, podocyte injury may be prominent in two major presentations: lupus podocytopathy and glomerular crescent formation, in which glomerular parietal epithelial cells play also a key role. We review here the contribution of podocyte impairment to different presentations of lupus nephritis, focusing on the podocyte signaling pathways involved in these lesions.

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De novo expression of podocyte proteins in parietal epithelial cells during experimental glomerular disease

AJP Renal Physiology ◽

10.1152/ajprenal.00428.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. F702-F711 ◽

Cited By ~ 72

Author(s):

Takamoto Ohse ◽

Michael R. Vaughan ◽

Jeffrey B. Kopp ◽

Ronald D. Krofft ◽

Caroline B. Marshall ◽

...

Keyword(s):

Epithelial Cells ◽

Basement Membrane ◽

Transforming Growth Factor ◽

Wilms Tumor ◽

Glomerular Disease ◽

Double Positive ◽

Specific Proteins ◽

Parietal Epithelial Cells ◽

Tgf Β1 ◽

Glomerular Tuft

Studies have shown that certain cells of the glomerular tuft begin to express proteins considered unique to other cell types upon injury. Little is known about the response of parietal epithelial cells (PEC) to injury. To determine whether PECs change their phenotype upon injury to also express proteins traditionally considered podocyte specific, the following four models of glomerular disease were studied: the transforming growth factor (TGF)-β1 transgenic mouse model of global glomerulosclerosis, the adriamycin model of focal segmental glomerulosclerosis (FSGS), the anti-glomerular basement membrane (GBM) model of crescentic glomerulonephritis, and the passive Heymann nephritis model of membranous nephropathy. Double immunostaining was performed with antibodies to podocyte-specific proteins (synaptopodin and Wilms' tumor 1) and antibodies to PEC specific proteins (paired box gene 8 and claudin-1). No double staining was detected in normal mice. In contrast, the results showed a statistical increase in the number of cells attached to Bowman basement membrane that were double-positive for both podocyte/PEC proteins in TGF-β;1 transgenic, anti-GBM, and membranous animals. Double-positive cells for both podocyte and PEC proteins were also statistically increased in the glomerular tuft in TGF-β1 transgenic, anti-GBM, and FSGS mice. These results are consistent with glomerular cells coexpressing podocyte and PEC proteins in experimental glomerular disease, but not under normal circumstances.

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Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS

AJP Renal Physiology ◽

10.1152/ajprenal.00020.2013 ◽

2013 ◽

Vol 304 (11) ◽

pp. F1375-F1389 ◽

Cited By ~ 67

Author(s):

Jiong Zhang ◽

Jeffrey W. Pippin ◽

Ronald D. Krofft ◽

Shokichi Naito ◽

Zhi-Hong Liu ◽

...

Keyword(s):

Epithelial Cells ◽

Cell Protein ◽

Abrupt Decrease ◽

Glomerular Cell ◽

Renal Progenitor Cells ◽

Glomerular Epithelial Cells ◽

Podocyte Loss ◽

Parietal Epithelial Cell ◽

Daily Prednisone ◽

Parietal Epithelial Cells

Prednisone is a mainstay of treatment for patients with focal segmental glomerulosclerosis (FSGS), a disease characterized by reduced podocyte number and glomerulosclerosis. Although the systemic immune-modulatory effects of prednisone are well-known, direct tissue effects on glomerular cells are poorly understood. Experimental FSGS was induced in mice with a cytotoxic anti-podocyte antibody, resulting in an abrupt decrease in podocyte number by day 3, proteinuria, and the development of glomerulosclerosis. Administering daily prednisone to mice with FSGS, beginning at day 3, significantly increased podocyte number at weeks 2 and 4. Podocyte number did not increase in control mice with FSGS given DMSO. The increase in podocyte number in prednisone-treated mice correlated significantly with reduced glomerulosclerosis. Prednisone reduced podocyte apoptosis measured by synaptopodin+/caspase-3+ double staining. Additionally, the number of podocyte progenitors, defined as cells expressing both a parietal epithelial cell protein and a podocyte protein, was significantly increased in prednisone-treated mice with FSGS at weeks 2 and 4. This was associated with increased phospho-ERK staining in both parietal epithelial cells (PAX2+/p-ERK+) and in podocyte progenitors (WT-1+/p-ERK+ lining Bowman's capsule). These data show that in this model of experimental FSGS, prednisone augments glomerular repair by increasing podocyte number through direct effects on both glomerular epithelial cells. Prednisone limits podocyte loss by reducing apoptosis, and it increases regeneration by augmenting the number of podocyte progenitors. The data support a direct glomerular cell action for prednisone in improving outcomes in FSGS.

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Mechanisms of Scarring in Focal Segmental Glomerulosclerosis

Kidney Diseases ◽

10.1159/000517108 ◽

2021 ◽

pp. 1-9

Author(s):

Ke Sun ◽

Qionghong Xie ◽

Chuan-Ming Hao

Keyword(s):

Epithelial Cells ◽

Influencing Factors ◽

Focal Segmental Glomerulosclerosis ◽

Therapeutic Strategies ◽

Podocyte Injury ◽

Segmental Glomerulosclerosis ◽

Potential Sources ◽

Histologic Pattern ◽

Parietal Epithelial Cells

Background: Focal segmental glomerulosclerosis (FSGS) is a histologic pattern characterized by focal glomerular scarring, which often progresses to systemic and diffuse glomerulosclerosis. Previous studies have emphasized that the initiation of classic FSGS occurs in podocytes. The dysfunction and loss of podocytes have been associated with the development of proteinuria and the progression of various diseases. In addition, primary, secondary, and genetic FSGS are caused by different mechanisms of podocyte injury. Summary: The potential sources and mechanism of podocyte supplementation are the focus of our current research. Increasing attention has been paid to the role played by parietal epithelial cells (PECs) during the progression of FSGS. PECs are not only the primary influencing factors in glomerulosclerosis lesions but also have repair abilities, which remain a focus of debate. Notably, other resident glomerular cells also play significant roles in the progression of this disease. Key Message: In this review, we focus on the mechanism of scarring in FSGS and discuss current and potential therapeutic strategies.

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P0407THE INVESTIGATION OF SYNAPTOPODIN EXPRESSION OF PODOCYTES IN GLOMERONEPHRITIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0407 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Zhigang Zhang

Keyword(s):

Molecular Mechanisms ◽

Cultured Cells ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Adriamycin Nephropathy ◽

Assembly Result ◽

And Function ◽

Rhoa Signaling ◽

New Strategies

Abstract Background and Aims Synaptopodin, a proline-rich actin-associated protein, plays an important role in the regulation of podocytes processes structures and dynamics. The mutation or lack of synaptopodin may lead to the changes of podocytes structures and functions and cause the occurrence of proteinuria. But the underlying molecular mechanisms remain primarily elusive. Method we used cellular and pathological experiments to observe the expression changes synaptopodin in vivo and vitrio. Results The results showed that the reduction expression of synaptopodin and RhoA were found in the podocytes in different nephriris of human renal biopsy as well as in rat adriamycin nephropathy. The cultured cells treated with inflammatory cytokins such as TNF, IL-1 also showed decreased synaptopodin level in podocyte, which led to low RhoA level and disarrange the actin cytoskeleton assembly, result in the abnormal changes of podocyte morphology. Conclusion These data preliminarily proved that synaptopodin loss in podocyte injury plays an important role in the regulation of podocyte morphology and function through RhoA signaling pathway, and further researches are required to clarify the more mechanism, which may provide new strategies and methods for the prevention and treatment of glomerular diseases.

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Potential Roles of Long Noncoding RNAs as Therapeutic Targets in Renal Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms21082698 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2698 ◽

Cited By ~ 4

Author(s):

Hyun Jin Jung ◽

Hyun-Ju Kim ◽

Kwan-Kyu Park

Keyword(s):

Renal Fibrosis ◽

Metabolic Diseases ◽

Noncoding Rnas ◽

Therapeutic Targets ◽

Long Noncoding Rnas ◽

Glomerular Diseases ◽

Kidney Fibrosis ◽

Regulatory Molecule ◽

And Function ◽

Role And Function

Many studies have made clear that most of the genome is transcribed into noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), both of which can affect different cell features. LncRNAs are long heterogeneous RNAs that regulate gene expression and a variety of signaling pathways involved in cellular homeostasis and development. Several studies have demonstrated that lncRNA is an important class of regulatory molecule that can be targeted to change cellular physiology and function. The expression or dysfunction of lncRNAs is closely related to various hereditary, autoimmune, and metabolic diseases, and tumors. Specifically, recent work has shown that lncRNAs have an important role in kidney pathogenesis. The effective roles of lncRNAs have been recognized in renal ischemia, injury, inflammation, fibrosis, glomerular diseases, renal transplantation, and renal-cell carcinoma. The present review focuses on the emerging role and function of lncRNAs in the pathogenesis of kidney inflammation and fibrosis as novel essential regulators. Although lncRNAs are important players in the initiation and progression of many pathological processes, their role in renal fibrosis remains unclear. This review summarizes the current understanding of lncRNAs in the pathogenesis of kidney fibrosis and elucidates the potential role of these novel regulatory molecules as therapeutic targets for the clinical treatment of kidney inflammation and fibrosis.

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Mechanisms of Scarring in Focal Segmental Glomerulosclerosis

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155419850170 ◽

2019 ◽

Vol 67 (9) ◽

pp. 623-632

Author(s):

Jianyong Zhong ◽

Jacob B. Whitman ◽

Hai-Chun Yang ◽

Agnes B. Fogo

Keyword(s):

Epithelial Cells ◽

Focal Segmental Glomerulosclerosis ◽

Genetic Mutation ◽

Tubular Epithelial Cells ◽

Podocyte Injury ◽

Segmental Glomerulosclerosis ◽

Initial Injury ◽

Parietal Epithelial Cells ◽

Initial Target ◽

Increased Susceptibility

Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is the initial target in primary FSGS, induced by a circulating factor. Several gene variants, for example, APOL1, are associated with increased susceptibility to FSGS. Primary FSGS may be due to genetic mutation in key podocyte genes. Increased work stress after loss of nephrons, epigenetic mechanisms, and various profibrotic pathways can contribute to progressive sclerosis, regardless of the initial injury. The progression of FSGS lesions also involves crosstalk between podocytes and other kidney cells, such as parietal epithelial cells, glomerular endothelial cells, and even tubular epithelial cells. New insights related to these mechanisms could potentially lead to new therapeutic strategies to prevent progression of FSGS.

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The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis

AJP Renal Physiology ◽

10.1152/ajprenal.00228.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. F98-F104 ◽

Cited By ~ 28

Author(s):

Kazuo Sakamoto ◽

Toshiharu Ueno ◽

Namiko Kobayashi ◽

Satoshi Hara ◽

Yasutoshi Takashima ◽

...

Keyword(s):

Epithelial Cells ◽

Focal Segmental Glomerulosclerosis ◽

Wilms Tumor ◽

Double Positive ◽

Segmental Glomerulosclerosis ◽

Injury Model ◽

Major Direction ◽

Parietal Epithelial Cell ◽

Parietal Epithelial Cells ◽

Phenotypic Transition

Focal segmental glomerulosclerosis (FSGS) is a podocyte disease. Among the various histologies of FSGS, active epithelial changes, hyperplasia, as typically seen in the collapsing variant, indicates disease progression. Using a podocyte-specific injury model of FSGS carrying a genetic podocyte tag combined with double immunostaining by different sets of podocytes and parietal epithelial cell (PEC) markers [nestin/Pax8, Wilms' tumor-1 (WT1)/claudin1, and podocalyxin/Pax2], we investigated the direction of epithelial phenotypic transition and its role in FSGS. FSGS mice showed progressive proteinuria and renal dysfunction often accompanied by epithelial hyperplasia, wherein 5-bromo-4-chloro-3-indoyl β-d-galactoside (X-gal)-positive podocyte-tagged cells were markedly decreased. The average numbers of double-positive cells in all sets of markers were significantly increased in the FSGS mice compared with the controls. In addition, the average numbers of double-positive cells for X-gal/Pax8, nestin/Pax8 and podocalyxin/Pax2 staining in the FSGS mice were comparable, whereas those of WT1/claudin1 were significantly increased. When we divided glomeruli from FSGS mice into those with FSGS lesions and those without, double-positive cells tended to be more closely associated with glomeruli without FSGS lesions compared with those with FSGS lesions. Moreover, the majority of double-positive cells appeared to be isolated and very rarely associated with FSGS lesions (1/1,997 glomeruli). This study is the first to show the incidence and localization of epithelial cells with phenotypical changes in FSGS using a genetic tag. The results suggest that the major direction of epithelial phenotypic transition in cellular FSGS is from podocytes to PECs and that these cells were less represented in the active lesions of FSGS.

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Podocytes and Proteinuric Kidney Disease

BANTAO Journal ◽

10.2478/bj-2014-0004 ◽

2015 ◽

Vol 12 (1) ◽

pp. 16-19

Author(s):

Alketa Koroshi ◽

Alma Idrizi

Keyword(s):

Treatment Strategies ◽

Glomerular Disease ◽

Glomerular Sclerosis ◽

Endstage Renal Disease ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Glomerular Function ◽

Podocyte Loss ◽

Insight Into

Abstract Glomerular disease is the most common cause of endstage renal disease (ESRD), accounting for almost two thirds of cases. In glomerular disease, alterations of po-docytes are of particular importance. Podocyte loss represents a central mediator of glomerular sclerosis. Toxic, genetic, immune, infectious, oxidant, metabolic, hemody-namic, and other mechanisms can all target the podo-cytes. These mechanisms provide new insight into the unique dynamic microenvironment that each individual podocyte inhabits and how it can turn hostile to survival. At the same time, they raise new therapeutic challenges to preserve glomerular function by containing podocyte injury and limiting its spread, both in podo-cytopathies and in other progressive glomerular diseases. Treatment strategies should aim at enhancing podocyte survival. The renin-angiotensin axis blockade, apart from its antifibrotic and intraglomerular hemodynamic effects, has an important role in preventing podocyte loss. However, only long-term observational studies can clarify if many patients will benefit from podocyte-targeted treatment such as abatacept or similar agents.

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