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Stem and progenitor cells have been observed to contribute to regenerative processes in acute renal failure and chronic kidney disease. Recent research has delved into the intricate mechanisms by which stem and progenitor cells exert their influence on kidney diseases. Understanding how these cells integrate with the existing renal architecture and their response to injury could pave the way for innovative treatment strategies aimed at promoting kidney repair and regeneration. Overall, the role of stem and progenitor cells in kidney diseases is multifaceted, with their ability to contribute to tissue regeneration, immune modulation, and the maintenance of renal homeostasis. Here, we review the studies that we have available today about the involvement of stem and progenitor cells both in regenerative therapies and in the causes of renal diseases, as well as in natural healing mechanisms, taking into account the main kidney disorders, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, C3 glomerulopathy, focal segmental glomerulosclerosis, idiopathic membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and ANCA-associated crescentic glomerulonephritis. Moreover, based on the comprehensive data available in the framework of the specific kidney diseases on stem cells and renal progenitors, we hypothesize a possible role of adult renal progenitors in exacerbating or recovering the illness. [ABSTRACT FROM AUTHOR]

Introduction: Acute kidney injury (AKI) is a common health problem that leads to high morbidity and potential mortality. The failure of conventional treatments to improve forms of this condition highlights the need for innovative and effective treatment approaches. Regenerative therapies with Renal Progenitor Cells (RPCs) have been proposed as a promising new strategy. A growing body of evidence suggests that progenitor cells differentiated from different sources, including human embryonic stem cells (hESCs), can effectively treat AKI. Methods: Here, we describe a method for generating RPCs and directed human Embryoid Bodies (EBs) towards CD133+CD24+ renal progenitor cells and evaluate their functional activity in alleviating AKI. Results: The obtained results show that hESCs-derived CD133+CD24+ RPCs can engraft into damaged renal tubules and restore renal function and structure in mice with gentamicin-induced kidney injury, and significantly decrease blood urea nitrogen levels, suppress oxidative stress and inflammation, and attenuate histopathological disturbances, including tubular necrosis, tubular dilation, urinary casts, and interstitial fibrosis. Conclusion: The results suggest that RPCs have a promising regenerative potential in improving renal disease and can lay the foundation for future cell therapy and disease modeling.

Background: Chronic kidney disease affects 10% of the world population, and it is associated with progression to end-stage kidney disease and increased morbidity and mortality. The advent of multi-omics technologies has expanded our knowledge on the complexity of kidney diseases, revealing their frequent genetic etiology, particularly in children and young subjects. Genetic heterogeneity and drug screening require patient-derived disease models to establish a correct diagnosis and evaluate new potential treatments and outcomes. Summary: Patient-derived renal progenitors can be isolated from urine to set up proper disease modeling. This strategy allows to make diagnosis of genetic kidney disease in patients carrying unknown significance variants or uncover variants missed from peripheral blood analysis. Furthermore, urinary-derived tubuloids obtained from renal progenitors of patients appear to be potentially valuable for modeling kidney diseases to test ex vivo treatment efficacy or to develop new therapeutic approaches. Finally, renal progenitors derived from urine can provide insights into acute kidney injury and predict kidney function recovery and outcome. Key Messages: Renal progenitors derived from urine are a promising new noninvasive and easy-to-handle tool, which improves the rate of diagnosis and the therapeutic choice, paving the way toward a personalized healthcare.

Abstract Background The glomerulus is a highly complex system, composed of different interdependent cell types that are subjected to various mechanical stimuli. These stimuli regulate multiple cellular functions, and changes in these functions may contribute to tissue damage and disease progression. To date, our understanding of the mechanobiology of glomerular cells is limited, with most research focused on the adaptive response of podocytes. However, it is crucial to recognize the interdependence between podocytes and parietal epithelial cells, in particular with the progenitor subset, as it plays a critical role in various manifestations of glomerular diseases. This highlights the necessity to implement the analysis of the effects of mechanical stress on renal progenitor cells. Methods Microgravity, modeled by Rotary Cell Culture System, has been employed as a system to investigate how renal progenitor cells respond to alterations in the mechanical cues within their microenvironment. Changes in cell phenotype, cytoskeleton organization, cell proliferation, cell adhesion and cell capacity for differentiation into podocytes were analyzed. Results In modeled microgravity conditions, renal progenitor cells showed altered cytoskeleton and focal adhesion organization associated with a reduction in cell proliferation, cell adhesion and spreading capacity. Moreover, mechanical forces appeared to be essential for renal progenitor differentiation into podocytes. Indeed, when renal progenitors were exposed to a differentiative agent in modeled microgravity conditions, it impaired the acquisition of a complex podocyte-like F-actin cytoskeleton and the expression of specific podocyte markers, such as nephrin and nestin. Importantly, the stabilization of the cytoskeleton with a calcineurin inhibitor, cyclosporine A, rescued the differentiation of renal progenitor cells into podocytes in modeled microgravity conditions. Conclusions Alterations in the organization of the renal progenitor cytoskeleton due to unloading conditions negatively affect the regenerative capacity of these cells. These findings strengthen the concept that changes in mechanical cues can initiate a pathophysiological process in the glomerulus, not only altering podocyte actin cytoskeleton, but also extending the detrimental effect to the renal progenitor population. This underscores the significance of the cytoskeleton as a druggable target for kidney diseases.

Background: Chronic kidney disease affects 10% of the world population, and it is associated with progression to end-stage kidney disease and increased morbidity and mortality. The advent of multi-omics technologies has expanded our knowledge on the complexity of kidney diseases, revealing their frequent genetic etiology, particularly in children and young subjects. Genetic heterogeneity and drug screening require patient-derived disease models to establish a correct diagnosis and evaluate new potential treatments and outcomes. Summary: Patient-derived renal progenitors can be isolated from urine to set up proper disease modeling. This strategy allows to make diagnosis of genetic kidney disease in patients carrying unknown significance variants or uncover variants missed from peripheral blood analysis. Furthermore, urinary-derived tubuloids obtained from renal progenitors of patients appear to be potentially valuable for modeling kidney diseases to test ex vivo treatment efficacy or to develop new therapeutic approaches. Finally, renal progenitors derived from urine can provide insights into acute kidney injury and predict kidney function recovery and outcome. Key Messages: Renal progenitors derived from urine are a promising new noninvasive and easy-to-handle tool, which improves the rate of diagnosis and the therapeutic choice, paving the way toward a personalized healthcare. [ABSTRACT FROM AUTHOR]

Stem and progenitor cells have been observed to contribute to regenerative processes in acute renal failure and chronic kidney disease. Recent research has delved into the intricate mechanisms by which stem and progenitor cells exert their influence on kidney diseases. Understanding how these cells integrate with the existing renal architecture and their response to injury could pave the way for innovative treatment strategies aimed at promoting kidney repair and regeneration. Overall, the role of stem and progenitor cells in kidney diseases is multifaceted, with their ability to contribute to tissue regeneration, immune modulation, and the maintenance of renal homeostasis. Here, we review the studies that we have available today about the involvement of stem and progenitor cells both in regenerative therapies and in the causes of renal diseases, as well as in natural healing mechanisms, taking into account the main kidney disorders, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, C3 glomerulopathy, focal segmental glomerulosclerosis, idiopathic membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and ANCA-associated crescentic glomerulonephritis. Moreover, based on the comprehensive data available in the framework of the specific kidney diseases on stem cells and renal progenitors, we hypothesize a possible role of adult renal progenitors in exacerbating or recovering the illness.

Introduction: Acute kidney injury (AKI) is a common health problem that leads to high morbidity and potential mortality. The failure of conventional treatments to improve forms of this condition highlights the need for innovative and effective treatment approaches. Regenerative therapies with Renal Progenitor Cells (RPCs) have been proposed as a promising new strategy. A growing body of evidence suggests that progenitor cells differentiated from different sources, including human embryonic stem cells (hESCs), can effectively treat AKI., Methods: Here, we describe a method for generating RPCs and directed human Embryoid Bodies (EBs) towards CD133+CD24 + renal progenitor cells and evaluate their functional activity in alleviating AKI., Results: The obtained results show that hESCs-derived CD133+CD24 + RPCs can engraft into damaged renal tubules and restore renal function and structure in mice with gentamicin-induced kidney injury, and significantly decrease blood urea nitrogen levels, suppress oxidative stress and inflammation, and attenuate histopathological disturbances, including tubular necrosis, tubular dilation, urinary casts, and interstitial fibrosis., Conclusion: The results suggest that RPCs have a promising regenerative potential in improving renal disease and can lay the foundation for future cell therapy and disease modeling., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Development of the metanephric kidney is strongly dependent on complex signaling pathways and cell–cell communication between at least four major progenitor cell populations (ureteric bud, nephron, stromal, and endothelial progenitors) in the nephrogenic zone. In recent years, the improvement of human-PSC-derived kidney organoids has opened new avenues of research on kidney development, physiology, and diseases. Moreover, the kidney organoids provide a three-dimensional (3D) in vitro model for the study of cell-cell and cell-matrix interactions in the developing kidney. In vitro re-creation of a higher-order and vascularized kidney with all of its complexity is a challenging issue; however, some progress has been made in the past decade. This review focuses on major signaling pathways and transcription factors that have been identified which coordinate cell fate determination required for kidney development. We discuss how an extensive knowledge of these complex biological mechanisms translated into the dish, thus allowed the establishment of 3D human-PSC-derived kidney organoids.

Aim: Herein we propose creating a bilayer tubular kidney in‐vitro model. It is hypothesized that membranes composed of decellularized porcine kidney extracellular matrix are valid substitutes of the tubular basement membrane by mimicking the physiological relevance of the in vivo environment and disease phenotypes. Methods: Extracellular matrix was obtained from decellularized porcine kidneys. After processing by lyophilization and milling, it was dissolved in an organic solvent and blended with poly(caprolactone). Porous membranes were obtained by electrospinning and seeded with human primary renal progenitor cells to evaluate phenotypic alterations. To create a bilayer model of the in vivo tubule, the same cells were differentiated into epithelial tubular cells and co‐cultured with endothelial cells in opposite sites. Results: Our results demonstrate increasing metabolic activity, proliferation and total protein content of renal progenitors over time. We confirmed the expression of several genes encoding epithelial transport proteins and we could also detect tubular‐specific proteins by immunofluorescence stainings. Functional and transport assays were performed trough the bilayer by quantifying both human serum albumin uptake and inulin leakage. Furthermore, we validated the chemical modulation of nephrotoxicity on this epithelium‐endothelium model by cisplatin exposure. Conclusion: The use of decellularized matrices in combination with primary renal cells was shown to be a valuable tool for modelling renal function and disease in vitro. We successfully validated our hypothesis by replicating the physiological conditions of an in vitro tubular bilayer model. The developed system may contribute significantly for the future investigation of advanced therapies for kidney diseases. [ABSTRACT FROM AUTHOR]

Human pluripotent stem cells (hPSCs) provide a source for the generation of defined kidney cells and renal organoids applicable in regenerative medicine, disease modeling, and drug screening. These applications require the provision of hPSC-derived renal cells by reproducible, scalable, and efficient methods. We established a chemically defined protocol by application of Activin A, BMP4, and Retinoic acid followed by GDNF, which steered hPSCs to the renal lineage and resulted in populations of SIX2+/CITED1+ metanephric mesenchyme- (MM) and of HOXB7+/GRHL2+ ureteric bud (UB)-like cells already by 6 days. Transcriptome analysis corroborated that the PSC-derived cell types at day 8 resemble their renal vesicle and ureteric epithelial counterpart in vivo, forming tubular and glomerular renal cells 6 days later. We demonstrate that starting from hPSCs, our in vitro protocol generates a pool of nephrogenic progenitors at the renal vesicle stage, which can be further directed into specialized nephronal cell types including mesangial-, proximal tubular-, distal tubular, collecting duct epithelial cells, and podocyte precursors after 14 days. This simple and rapid method to produce renal cells from a common precursor pool in 2D culture provides the basis for scaled-up production of tailored renal cell types, which are applicable for drug testing or cell-based regenerative therapies. [ABSTRACT FROM AUTHOR]

Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-like receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single-cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic.

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.

Often the cause of refractory lupus nephritis (RLN) remains unclear. We performed next-generation sequencing for podocyte genes in an RLN patient and identified compound heterozygosity for APOL1 risk alleles G1 and G2 and a novel homozygous c.[1049C>T]+[1049C>T] NPHS1 gene variant of unknown significance. To test for causality renal progenitor cells isolated from urine of this patient were differentiated into podocytes in vitro. Podocytes revealed aberrant nephrin trafficking, cytoskeletal structure and lysosomal leakage, and increased detachment as compared with podocytes isolated from controls. Thus, lupus podocytopathy can be confirmed as a cause of RLNby functional genetics on patient-derived podocytes. [ABSTRACT FROM AUTHOR]

Rationale: Mammalian renal proximal tubules can partially regenerate after acute kidney injury (AKI). However, cells participating in the renal proximal tubule regeneration remain to be elucidated. Wilms' tumor 1 (WT1) expresses in a subtype of glomeruli parietal epithelial cells (PECs) in adult kidneys, it remains unclear whether these WT1 + PECs play a role in renal regeneration/repair after AKI. Methods: Ischemia-reperfusion injury (IRI) mouse model was used to investigate the expression pattern of WT1 in the kidney after severe AKI. Conditional deletion of WT1 gene mice were generated using Pax8 CreERT2 and WT1 fl/fl mice to examine the function of WT1. Then, genetic cell lineage tracing and single-cell RNA sequencing were performed to illustrate that WT1 + PECs develop into WT1 + proximal tubular epithelial cells (PTECs). Furthermore, in vitro clonogenicity, direct differentiation analysis and in vivo transplantation were used to reveal the stem cell-like properties of these WT1 + PECs. Results: The expression of WT1 protein in PECs and PTECs was increased after severe AKI. Conditional deletion of WT1 gene in PTECs and PECs aggravated renal tubular injury after severe AKI. WT1 + PECs develop into WT1 + PTECs via the transient scattered tubular cell stage, and these WT1 + PECs possess specific stem cell-like properties. Conclusions: We discovered a group of WT1 + PECs that promote renal proximal tubule regeneration/repair after severe AKI, and the expression of WT1 in PECs and PTECs is essential for renal proximal tubule regeneration after severe kidney injury., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: For many years, the glomerulus was considered incapable of regeneration. However, experimental and clinical evidence challenged this concept and showed that glomerular injury and even glomerulosclerosis can undergo regression under certain circumstances. The problem with glomerular regeneration is centered around the podocyte, a highly specialized cell that is the critical constituent of the glomerular filtration barrier. Summary: Podocytes are characterized by a complex cytoskeleton that makes them unable to proliferate. Thus, once their depletion reaches a specific threshold, it is considered to be irreversible. The discovery of cells with the aptitude to differentiate into podocytes in the adult kidney, i.e. renal progenitor cells (RPCs), was a critical step in understanding the mechanisms of glomerular repair. Accumulating evidence suggests that a tight regulation of many different signaling pathways, such as Notch, Wnt, and microRNA, is involved in a correct regenerative process and that an altered regulation of these same signaling pathways in RPCs triggers the generation of focal segmental glomerulosclerosis lesions. In particular, regeneration is severely impaired by proteinuria, when albumin sequesters retinoic acid and blocks RPC differentiation in podocytes. Key Messages: RPC maintenance and differentiating potential are regulated by complex mechanisms that can be implemented following glomerular injury and can be manipulated to activate regeneration for therapeutic purposes. A better understanding of the phenomenon of glomerular regeneration paves the way for the prevention and treatment of glomerular diseases. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The incidence of kidney diseases is increasing worldwide and they are emerging as a major public health problem. Once mostly considered inexorable, renal disease progression can now be halted and lesions can even regress with drugs such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II type I receptor blockers, indicating the possibility of kidney repair. Summary: The discovery of renal progenitor cells lining the Bowman capsule of adult rat and human kidneys has shed light on the mechanism of repair by ACEi. Parietal progenitors are a reservoir of cells that contribute to podocyte turnover in physiological conditions. In the early phases of renal disease these progenitors migrate chaotically and subsequently proliferate, accumulating in Bowman's space. The abnormal behavior of parietal progenitors is sustained by the activation of CXCR4 receptors in response to an increased production of the chemokine SDF-1 by podocytes activated by the inflammatory environment. Ang II, via the AT1 receptor, also contributes to progenitor cell proliferation. The CXCR4/SDF-1 and Ang II/AT1 receptor pathogenic pathways both pave the way for lesion formation and subsequent sclerosis. ACEi normalize the CXCR4 and AT1 receptor expression on progenitors, limiting their proliferation, concomitant with the regression of hyperplastic lesions in animals, and in a patient with crescentic glomerulopathy. Key Message: Understanding the molecular and cellular determinants of regeneration triggered by renoprotective drugs will reveal novel pathways that might be challenged or targeted by pharmacological therapy. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Nephropathies arise from conditions that alter nephron development or trigger nephron damage during neonatal, juvenile, and adult stages of life. Much evidence suggests that a key role in maintaining kidney integrity, homeostasis, and regenerative capacity is played by a population of progenitor cells resident in the organ. Although the primary goals in the field of renal progenitor cells are understanding their ability to regenerate nephrons and to restore damaged kidney function, the discovery of these cells could also be used to elucidate the molecular and pathophysiological basis of kidney diseases. As a result, once the identification of a subset of progenitor cells capable of kidney regeneration has been obtained, the increasing knowledge about their characteristics and about the mechanisms of renal development had pointed out the possibility of understanding the molecular basis of kidney diseases, so that, nowadays, some renal disorders could also be related to renal progenitor dysfunction. In this review, we summarize the evidence on the existence of renal progenitors in fetal and adult kidneys and discuss their role in physiology as well as in the pathogenesis of renal disorders with a particular focus on childhood age. [ABSTRACT FROM AUTHOR]

Regeneration can occur through multiple distinct mechanisms, such as pluripotent stem cells, lineage-committed progenitors or dedifferentiation. The respective contribution of each of these regenerative strategies in every organ or tissue may be different. Recent results indicate that dedifferentiation contributes less than previously thought, and that stem or progenitor cells seem to be the main drivers of regenerative processes. Our views of regeneration in the kidney are undergoing the same process of revision. Indeed, studies in humans have established the existence of a scattered population of tubular progenitors in the adult kidney. Renal progenitors have been discovered also in other animal classes such as fish and insects. In contrast, in rodents a tubular progenitor phenotype seems to be induced only after tubular injury, suggesting some differences may exist. Is this difference really related to a distinct regenerative strategy or is it simply a matter of the type and modality of cellular markers expressed? It may also be possible that progenitor cells, as well as tubular cell dedifferentiation, act in concert to allow regeneration of a complex organ like the adult mammalian kidney, as recently proposed also for the liver. Further studies are needed to resolve the riddle of tubular regeneration. However, beyond the controversial results obtained from humans and rodents, identification of tubular progenitors in humans can move the field forward and provide a novel perspective for understanding tubular regeneration. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Recent studies implicated the existence in adult human kidney of a population of renal progenitors with the potential to regenerate glomerular as well as tubular epithelial cells and characterized by coexpression of surface markers CD133 and CD24. Here, we demonstrate that CD133+CD24+ renal progenitors can be distinguished in distinct subpopulations from normal human kidneys based on the surface expression of vascular cell adhesion molecule 1, also known as CD106. CD133+CD24+CD106+ cells were localized at the urinary pole of Bowman's capsule, while a distinct population of scattered CD133+CD24+CD106− cells was localized in the proximal tubule as well as in the distal convoluted tubule. CD133+CD24+CD106+ cells exhibited a high proliferative rate and could differentiate toward the podocyte as well as the tubular lineage. By contrast, CD133+CD24+CD106− cells showed a lower proliferative capacity and displayed a committed phenotype toward the tubular lineage. Both CD133+CD24+CD106+ and CD133+CD24+CD106− cells showed higher resistance to injurious agents in comparison to all other differentiated cells of the kidney. Once injected in SCID mice affected by acute tubular injury, both of these populations displayed the capacity to engraft within the kidney, generate novel tubular cells, and improve renal function. These properties were not shared by other tubular cells of the adult kidney. Finally, CD133+CD24+CD106− cells proliferated upon tubular injury, becoming the predominating part of the regenerating epithelium in patients with acute or chronic tubular damage. These data suggest that CD133+CD24+CD106− cells represent tubular-committed progenitors that display resistance to apoptotic stimuli and exert regenerative potential for injured tubular tissue. S TEM C ELLS 2012;30:1714-1725 [ABSTRACT FROM AUTHOR]

Glomerular diseases account for 90% of end-stage kidney disease. Podocyte loss is a common determining factor for the progression toward glomerulosclerosis. Mature podocytes cannot proliferate, but recent evidence suggests that they can be replaced by renal progenitors localized within the Bowman's capsule. Here, we demonstrate that Notch activation in human renal progenitors stimulates entry into the S-phase of the cell cycle and cell division, whereas its downregulation is required for differentiation toward the podocyte lineage. Indeed, a persistent activation of the Notch pathway induced podocytes to cross the G2/M checkpoint, resulting in cytoskeleton disruption and death by mitotic catastrophe. Notch expression was virtually absent in the glomeruli of healthy adult kidneys, while a strong upregulation was observed in renal progenitors and podocytes in patients affected by glomerular disorders. Accordingly, inhibition of the Notch pathway in mouse models of focal segmental glomerulosclerosis ameliorated proteinuria and reduced podocyte loss during the initial phases of glomerular injury, while inducing reduction of progenitor proliferation during the regenerative phases of glomerular injury with worsening of proteinuria and glomerulosclerosis. Taken altogether, these results suggest that the severity of glomerular disorders depends on the Notch-regulated balance between podocyte death and regeneration provided by renal progenitors. STEM CELLS 2010; 28:1674-1685. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is a leading cause of mortality and morbidity in Western countries and is estimated to affect 11% of the adult population. The possibility of treatment of chronic kidney disease has been severely impaired by our poor knowledge of the regenerative properties of the kidney. Recent results obtained in humans, together with genetic tagging experiments performed in rodents, demonstrated that the epithelial components of the cortical neph- ron share a unique progenitor, which can generate podocytes as well as tubular cells. Accordingly, lineage tracing experiments demonstrated that bone marrow- derived interstitial or papillary cells are not involved in the repair of injured adult renal epithelium. In addition, assessment of the markers CD24 and CD133 in adult human kidney as well as genetic tagging in rodents allowed us to identify a hierarchical population of renal progenitors arranged in a precise sequence within Bowman's capsule. The results of all of these studies suggest that the kidney contains a "renopoietic system," with a progenitor localized at the urinary pole of Bowman's capsule, from where it can initiate the replacement and regeneration of glomerular, as well as tubular, epithelial cells. Knowledge of renal progenitor cell biology may enable a better comprehension of the mechanisms of renal repair as well as more effective targeted therapies for acute and chronic kidney diseases. Stem Cells 2009;27-.2247-2253 [ABSTRACT FROM AUTHOR]

Background: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms., Methods: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids., Results: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury., Conclusions: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection., (Copyright © 2021 by the American Society of Nephrology.)

Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-like receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single-cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic. [ABSTRACT FROM AUTHOR]

Development of the metanephric kidney is strongly dependent on complex signaling pathways and cell-cell communication between at least four major progenitor cell populations (ureteric bud, nephron, stromal, and endothelial progenitors) in the nephrogenic zone. In recent years, the improvement of human-PSC-derived kidney organoids has opened new avenues of research on kidney development, physiology, and diseases. Moreover, the kidney organoids provide a three-dimensional (3D) in vitro model for the study of cell-cell and cell-matrix interactions in the developing kidney. In vitro re-creation of a higher-order and vascularized kidney with all of its complexity is a challenging issue; however, some progress has been made in the past decade. This review focuses on major signaling pathways and transcription factors that have been identified which coordinate cell fate determination required for kidney development. We discuss how an extensive knowledge of these complex biological mechanisms translated into the dish, thus allowed the establishment of 3D human-PSC-derived kidney organoids., (Copyright © 2020 Khoshdel Rad, Aghdami and Moghadasali.)

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI. [ABSTRACT FROM AUTHOR]

Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre , and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)