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Renin producing vascular smooth muscle cells activate WT1 and PECs upregulate PAX2 in adult glomerular disease with podocyte loss (A) Split panel images of a glomerulus following administration of anti-podocyte antibodies showing de novo expression of WT1 in the renin producing cells of the JGA (arrowhead). In addition to expression of WT1 in podocytes attached to the tuft, WT1 can also be seen in some PECs (arrows). (B) Images of normal and diseased glomeruli following anti-podocyte antibody administration. Note increased expression intensity of PAX2 in PECs
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The very limited ability of adult podocytes to proliferate in vivo is clinically significant because: podocytes form a vascular barrier which is functionally critical to the nephron; podocyte hypoplasia is a characteristic of disease; and inadequate regeneration of podocytes is a major cause of persistent podocyte hypoplasia. Excessive podocyte los...
Citations
... Additionally, impaired endocytosis leads to abnormal turnover of SD components thereby resulting in SD injury and proteinuria [26,27]. The exposed GBM lacking of podocytes coverage can adhere to the Bowman's capsule thus resulting in the occurrence of FSGS [3,28]. ...
Proteinuria is a common and important clinical manifestation of chronic kidney disease (CKD) and an independent risk factor for the progression of kidney disease. As a component of the glomerular filtration barrier (GFB), podocyte plays a key role in the pathogenesis of glomerular diseases and proteinuria. However, the pathophysiology of glomerular diseases associated with mitochondrial function is incompletely understood. Here, we identified three novel mutations in MTX2, encoding a membrane protein in mitochondria, associated with multisystem manifestations including nephrotic proteinuria and kidney injury in two Chinese patients. Conditional podocyte-specific Mtx2 knockout (Pod-Mtx2-KO) mice present a series of podocyte and glomerular abnormalities from 8 weeks to old age, including microalbuminuria, glomerular mesangial hyperplasia, fusion and effacement of foot process. MTX2 deficiency impaired podocyte functions in vitro, manifested by reductions of adhesion, migration and endocytosis, which were further restored by overexpression of MTX2. Moreover, MTX2 defects led to abnormal mitochondrial structure and dysfunction, evidenced with defects of complex I and III, increased production of reactive oxygen species (ROS), and decreased protein levels of Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex which is responsible for maintaining mitochondrial cristae morphology. Collectively, these findings reveal that the normal expression of MTX2 in glomerulus plays an important role in the adhesion, migration, endocytosis, proliferation and other physiological functions of podocytes, which may be realized by maintaining the morphological structure and function of mitochondria. Abnormal expression of MTX2 can lead to mitochondrial dysfunction and structural abnormalities by Sam50-CHCHD3-Mitofilin axis in podocyte, which further induces podocyte injury, glomerular lesions and proteinuria.
... Podocyte to parietal epithelial cell communication is wellcharacterized and has major implications for kidney pathogenesis. Originating from similar mesenchymal progenitors, these two cell types differentiate from one another through activation of cell-type-specific genes during the early stages of nephrogenesis (97). In the setting of podocyte hypoplasia, a characteristic of many glomerular diseases, podocytes are lost and inadequate regeneration occurs. ...
Podocytes are highly specialized epithelial cells that surround the capillaries of the glomeruli in the kidney. Together with the glomerular endothelial cells, these post-mitotic cells are responsible for regulating filtrate from the circulating blood with their organized network of interdigitating foot processes that wrap around the glomerular basement membrane. While podocyte injury and subsequent loss is the hallmark of many glomerular diseases, recent evidence suggests that the cell-cell communication between podocytes and other glomerular and non-glomerular cells is critical for the development and progression of kidney disease. In this review, we highlight these key cellular pathways of communication and how they might be a potential target for the therapy in glomerular disease. We also postulate that podocytes might serve as a central hub for communication in the kidney under basal conditions and in response to cellular stress, which may have implications in the development and progression of glomerular diseases.
... Consequently, podocytes continue to be regarded as terminally differentiated epithelial cells, characterized by an intrinsic limitation in their proliferative capacity. 7,49 Therefore, preventing the loss of podocytes in LN patients is paramount for the preservation of barrier integrity and overall renal microenvironment homeostasis ( Figure 1). ...
Lupus nephritis (LN), an immune complex‐mediated glomerulonephritis, is one of the most severe complications of systemic lupus erythematosus. Current therapeutic regimens for LN mainly involve nonspecific immunosuppressants and biologics targeting immune cells, but these treatments are not always effective and some patients are nonresponsive and susceptible to recurrence. Podocytes are essential for maintaining the glomerular filtration barrier. Injury to and loss of podocytes lead to proteinuria, a hallmark of renal involvement and LN. Podocytes are, therefore, emerging as prospective therapeutic targets for LN. There are numerous mechanisms underlying podocyte malfunction in LN, with autophagy, mitochondrial dysregulation, and programmed cell death being the main processes behind podocyte loss. This review summarizes recent advances in understanding podocyte dysfunction in LN pathogenesis and discusses potential therapeutic interventions targeting podocytes in LN.
... miR193a is a negative regulator of Wilms' tumor protein 1 (WT-1) [14]. WT-1 is a marker of mature podocytes and a crucial transcription factor converting mesenchymal progenitors towards podocyte phenotype during nephrogenesis [61]. WT1 also forms a repressor complex on the promoter site of the PAX2 gene and causes downregulation of the PEC phenotype [17]; therefore, the downregulation of WT1 from elevated miR193a in precursor progenitor cells likely enhances the expression of PAX2 and PEC phenotype. ...
Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms’ tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a.
... Interestingly, we did not observe proteinuria in Zeb2 cKO mice (Supplementary Figure 2A), suggesting that glomerular filtration barrier was preserved in these mice. As FOXD1 is also active late in development in podocytes (41,42), we analyzed the expressions of nephrin and podocin, two podocyte markers in ...
FOXD1+ derived stromal cells give rise to pericytes and fibroblasts that support the kidney vasculature and interstitium but are also major precursors of myofibroblasts. ZEB2 is a SMAD-interacting transcription factor that is expressed in developing kidney stromal progenitors. Here we show that Zeb2 is essential for normal FOXD1+ stromal progenitor development. Specific deletion of mouse Zeb2 in FOXD1+ stromal progenitors (Zeb2 cKO) leads to abnormal interstitial stromal cell development, differentiation, and kidney fibrosis. Immunofluorescent staining analyses revealed abnormal expression of interstitial stromal cell markers MEIS1/2/3, CDKN1C, and CSPG4 (NG2) in newborn and 3-week-old Zeb2 cKO mouse kidneys. Zeb2 deficient FOXD1+ stromal progenitors also took on a myofibroblast fate that led to kidney fibrosis and kidney failure. Cell marker studies further confirmed that these myofibroblasts expressed pericyte and resident fibroblast markers including PDGFRβ, CSPG4, Desmin, GLI1, and NT5E. Notably, increased interstitial collagen deposition associated with loss of Zeb2 in FOXD1+ stromal progenitors was accompanied by increased expression of activated SMAD1/5/8, SMAD2/3, SMAD4, and AXIN2. Thus, our study identifies a key role of ZEB2 in maintaining the cell fate of FOXD1+ stromal progenitors during kidney development whereas loss of ZEB2 leads to differentiation of FOXD1+ stromal progenitors into myofibroblasts and kidney fibrosis.
... Additionally, compared with healthy volunteers, podocyturia is 3.6-fold greater in patients with FD. [48] There is a significant inverse correlation between podocyturia and eGFR in male patients with FD, and a significant direct correlation with urinary protein creatinine ratio in all patients with FD [48]. Podocytes have a limited capacity to regenerate, therefore, the loss of podocytes in FD and subsequent glomerulosclerosis is indicative of irreversible nephron injury and loss of kidney function [48,74]. ...
Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.
... При ишемическом повреждении в большей степени страдают извитые канальцы, что и определяет большую стимуляцию пролиферации их эпителия [37]. Кроме того, регенерационный потенциал эпителиальных клеток почечных канальцев существенно выше, чем клеток почечных клубочков, в которых основным источником пролиферирующих клеток являются преимущественно подоциты и в меньшей степени париетальные эпителиальные клетки наружного слоя капсулы Боумена [39,40]. Именно в этих зонах мы выявляли отдельные меченые Ki-67 клетки Сохранение клубочкового аппарата при ишемическом повреждении может происходить не только через стимуляцию регенерации клубочковых клеток, но и за счет уменьшения их повреждения, в том числе за счет подавления активности апоптоза. ...
Introduction. Currently, the possibilities of cell therapy using stem cells for the correction of functional disorders of organs, including kidneys, are being widely investigated. The main mechanism of action of stem cells is considered to be the activation of cellular regeneration and the inhibition of apoptosis by the products of their secretion (secretome), which makes it necessary to study the mechanisms of action of the stem cells secretome. Aim of study. To study the relationship of the nephroprotective effect of the drug, which is a protein-peptide secretom of embryonic brain cells (SESC), with its effect on the regeneration of kidney cells damaged by ischemia and the activity of their apoptosis. Material and methods. Experiments were carried out on 40 mongrel male rats weighing 280-320 g. Acute kidney injury of varying severity was caused by removal of the right kidney and ischemia of the remaining left kidney for 60 minutes or 90 minutes (20 rats per group). In each of these groups, 10 rats were injected daily subcutaneously with SESC at a dose of 0.1 ml/kg (10 injections), and the other 10 rats were not treated. After 3, 7 and 14 days, the ischemic kidney was removed and subjected to histological examination and histochemical determination of the expression of the proliferation marker Ki-67 and the anti-apoptotic protein Bcl-2 in the kidney structures. Results. In the treatment of SESC, up to 20% of hypertrophied renal glomeruli were detected already on the 3rd day in the absence of glomeruli with glomerulosclerosis, whereas in control experiments at this time hypertrophied glomeruli were not detected, and the proportion of glomeruli with signs of glomerulosclerosis was 5-10%. On the 7th and 14th days in both groups, the proportion of hypertrophied glomeruli increased, being compared in the group with 60-minute ischemia, but maintaining higher values in experiments with 90-minute ischemia and SESC therapy compared with the control. Glomeruli with glomerulosclerosis were significantly less frequently detected in the treatment of SESC, regardless of the severity of ischemic damage. At the same time, the expression of Bcl-2 in renal glomerular cells during SESC therapy decreased significantly to a lesser extent than in control experiments, confirming the relationship of inhibition of apoptosis during SESC therapy with inhibition of the development of sclerotic processes. A significant increase in the number of epithelial cells expressing the proliferation marker Ki-67 on the 3rd day, followed by a gradual decrease in their number, was detected in the renal tubules during SESC therapy, whereas in the control an increase in the number of labeled cells occurred only on the 7th and 14th days. With an increase in the severity of ischemic damage, the proliferation-stimulating effect of SESC was prolonged up to 14 days. The proliferative effect of SESC therapy was accompanied by a decrease in damage to the renal tubules, and the percentage of tubules with necrotic epithelium progressively decreased from 3-5% to 0-1% with an increase in the period after the start of therapy (7 and 14 days), indicating epithelial regeneration, while in the control their proportion remained at a higher level. Conclusion. Stimulation of cell proliferation and inhibition of apoptosis of damaged cells play an essential role in the nephroprotective effect of SESC, as in stem cells.
... ACE inhibitors [147], retinoids [148] or corticosteroids [149] increased podocyte numbers after depletion in the absence of proliferation, suggesting another cell source for novel podocytes. A bone marrow origin of circulating progenitors for podocytes is not clearly substantiated in experimental and human disease [150]. Podocytes and PECs originate from the same pool of mesenchymal cells and PECs could return to a fetal developmental reprogramming and become podocytes [151]. ...
Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance.
... Upregulated WT1 serves important roles in the differentiation of PECs toward podocytes [58,59]. In addition, WT1 inhibits Wnt/β-catenin signaling [60], which is considered a prerequisite for the differentiation of PECs to podocytes. ...
Podocytes 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.
... The complications of tissue injury and reduced tissue regeneration are important contributors to morbidity in patients suffering from kidney diseases. The long-term consequences of tissue damage are particularly apparent in the kidney's filtration system due to the low regenerative capacity, especially of podocytes (Nagata et al. 1998;Wanner et al. 2014;Shankland et al. 2014). The tubular compartment, albeit being capable of dedifferentiation and repopulation of damaged structures, can also be overcome by severe or prolonged disease courses, leading to interstitial fibrosis and tubular atrophy. ...
Acute and chronic kidney diseases are major contributors to morbidity and mortality in the global population. Many nephropathies are considered to be immune-mediated with dysregulated immune responses playing an important role in the pathogenesis. At present, targeted approaches for many kidney diseases are still lacking, as the underlying mechanisms remain insufficiently understood. With the recent development of organoids—a three-dimensional, multicellular culture system, which recapitulates important aspects of human tissues—new opportunities to investigate interactions between renal cells and immune cells in the pathogenesis of kidney diseases arise. To date, kidney organoid systems, which reflect the structure and closer resemble critical aspects of the organ, have been established. Here, we highlight the recent advances in the development of kidney organoid models, including pluripotent stem cell-derived kidney organoids and primary epithelial cell-based tubuloids. The employment and further required advances of current organoid models are discussed to investigate the role of the immune system in renal tissue development, regeneration, and inflammation to identify targets for the development of novel therapeutic approaches of immune-mediated kidney diseases.
