• Humans
• Kidney Glomerulus/physiopathology
• Kidney Glomerulus/pathology
• Kidney Tubules/physiopathology
• Kidney Tubules/pathology
• Animals
• Podocytes
• Kidney Diseases/physiopathology
• Kidney Diseases/pathology

• PECs
• exosomes
• fibrosis
• miRNA

• Animals
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Mice
• Fibrosis/metabolism
• Exosomes/metabolism
• Epithelial Cells/metabolism
• Receptor, Transforming Growth Factor-beta Type I/metabolism
• Receptor, Transforming Growth Factor-beta Type I/genetics
• Humans
• Male
• Ureteral Obstruction/metabolism
• Ureteral Obstruction/pathology
• Transcription Factors/metabolism
• Transcription Factors/genetics
• Mice, Inbred C57BL
• DNA-Binding Proteins/metabolism
• DNA-Binding Proteins/genetics
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Kidney Diseases/genetics
• Transforming Growth Factor beta1/metabolism
• Cell Line

• 81970610 NSFC | National Natural Science Foundation of China
• 22140903900 the Natural Science Foundation of Shanghai
• 22XD1431400 the Program of Shanghai Academic/Technology Researcher Leader
• 20172015 the Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant
• 82000634 National Natural Science Foundation of China
• 20YF1425000 Shanghai Sailing Program

• CSF-1R
• FSGS
• aPECs
• podocytes

• Glomerulosclerosis, Focal Segmental/pathology
• Glomerulosclerosis, Focal Segmental/metabolism
• Glomerulosclerosis, Focal Segmental/genetics
• Animals
• Humans
• Podocytes/metabolism
• Podocytes/pathology
• Macrophage Colony-Stimulating Factor/metabolism
• Macrophage Colony-Stimulating Factor/genetics
• Hyaluronan Receptors/metabolism
• Hyaluronan Receptors/genetics
• Mice
• Cell Proliferation/drug effects
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Epithelial Cells/drug effects
• Receptor, Macrophage Colony-Stimulating Factor/metabolism
• Receptor, Macrophage Colony-Stimulating Factor/genetics
• Kidney Glomerulus/pathology
• Kidney Glomerulus/metabolism
• Male
• Disease Models, Animal
• Cells, Cultured
• Female
• Up-Regulation
• Cell Movement/drug effects
• MAP Kinase Signaling System/drug effects
• Signal Transduction
• Mice, Inbred C57BL
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

• Antibody-mediated rejection
• Calcineurin-inhibitor
• Colombia classification
• Focal segmental glomerulosclerosis
• Recurrence
• Renal transplant biopsy

• Humans
• Glomerulosclerosis, Focal Segmental/complications
• Glomerulosclerosis, Focal Segmental/pathology
• Kidney Transplantation/adverse effects
• Kidney/pathology
• Kidney Glomerulus/pathology
• Antibodies
• Allografts/pathology

• 20K07418 Japan Society for the Promotion of Science

• Bile acid
• Metabolomics
• Obesity-related glomerulopathy
• Wen-Shen-Jian-Pi-Hua-Tan decoction

• podocyte
• parietal epithelial cell
• glomerulus
• fsgs
• gn
• crescent
• pseudocrescents

• Humans
• Podocytes/metabolism
• Glomerulosclerosis, Focal Segmental/pathology
• Kidney Glomerulus/pathology
• Bowman Capsule/metabolism
• Bowman Capsule/pathology
• Epithelial Cells/metabolism

• I01 BX003698 BLRD VA
• I01 BX005300 BLRD VA
• R01 DK112984 NIDDK NIH HHS
• R01 DK121846 NIDDK NIH HHS

• Acute kidney injury
• effacement of foot processes
• podocyte hyperplasia
• podocytopathy
• proteinuria
• thrombotic microangiopathy

• acute kidney injury
• cell division

• developmental programming
• diabetes
• hyperglycemia
• kidney
• nephron
• podocyte endowment

• Mice
• Animals
• Male
• Female
• Podocytes
• Albuminuria
• Mice, Inbred C57BL
• Diabetes Mellitus
• Hyperglycemia
• Renal Insufficiency, Chronic

• Acute kidney injury
• Repair
• Single-nucleus RNA sequencing
• Stemness

During human kidney development, cells of the proximal nephron gradually differentiate into podocytes and parietal epithelial cells (PECs). Podocytes are terminally differentiated cells that play a key role in both normal and pathological kidney function. Therefore, the potential of podocytes to regenerate or be replaced by other cell populations (PECs) is of great interest for the possible treatment of kidney diseases. In the present study, we analyzed the proliferation and differentiation capabilities of podocytes and PECs, changes in the expression pattern of nestin, and several early proteins including WNT4, Notch2, and Snail, as well as Ki-67, in tissues of developing, postnatal, and pathologically changed human kidneys by using immunohistochemistry and electron microscopy. Developing PECs showed a higher proliferation rate than podocytes, whereas nestin expression characterized only podocytes and pathologically changed kidneys. In the developing kidneys, WNT4 and Notch2 expression increased moderately in podocytes and strongly in PECs, whereas Snail increased only in PECs in the later fetal period. During human kidney development, WNT4, Notch2, and Snail are involved in early nephrogenesis control. In kidneys affected by congenital nephrotic syndrome of the Finnish type (CNF) and focal segmental glomerulosclerosis (FSGS), WNT4 decreased in both cell populations, whereas Notch2 decreased in FSGS. In contrast, Snail increased both in CNF and FSGS, whereas Notch2 increased only in CNF. Electron microscopy revealed cytoplasmic processes spanning the urinary space between the podocytes and PECs in developing and healthy postnatal kidneys, whereas the CNF and FSGS kidneys were characterized by numerous cellular bridges containing cells with strong expression of nestin and all analyzed proteins. Our results indicate that the mechanisms of gene control in nephrogenesis are reactivated under pathological conditions. These mechanisms could have a role in restoring glomerular integrity by potentially inducing the regeneration of podocytes from PECs.

Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.

• IgA glomerulonephritis
• diabetic nephropathy
• extracellular vesicles
• focal and segmental glomerulosclerosis
• glomerulonephritis
• lupus nephritis
• regenerative medicine
• stem cells
• vasculitis

• Endothelial Cells
• Extracellular Vesicles/metabolism
• Glomerulonephritis/metabolism
• Glomerulonephritis/therapy
• Humans
• Regenerative Medicine/methods
• Stem Cells/metabolism

• Natural Science Foundation of Guangdong Province
• National Natural Science Foundation of China
• Zhanjiang Science and Technology Bureau

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.

• acute kidney injury
• cell death
• chronic kidney disease
• kidney
• molecular mechanisms
• regeneration
• treatment

• Obesity
• actin cytoskeleton
• focal segmental glomerulosclerosis
• glomerulus
• nephrotic syndrome
• obesity-related glomerulopathy
• podocytes
• podocytopathy
• proteinuria

• crosstalk
• diabetic kidney disease
• glomerulus
• single-cell RNA sequencing
• tubular epithelial cell

Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain–derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, which include apoptosis, phenotype transformation, and secretion of extracellular matrix components and metalloproteinases. Monoclonal light chains associated with AL-Am but not those producing LCDD are avidly endocytosed by mesangial cells and delivered to the mature lysosomal compartment where amyloid fibrils are formed. Light chains from patients with LCDD exert their pathogenic signaling effect at the cell surface of mesangial cells. These events are generic mesangial responses to a variety of adverse stimuli, and they are similar to those characterizing other more frequent glomerulopathies responsible for many cases of end-stage renal disease. The pathophysiologic events that have been elucidated allow to propose future therapeutic approaches aimed at preventing, stopping, ameliorating, or reversing the adverse effects resulting from the interactions between glomerulopathic light chains and mesangium.

• AL-amyloidosis
• kidney
• kidney repair
• light chain deposition disease
• mesangium
• monoclonal Ig deposition disease
• monoclonal light chains
• stem cells

• Ectopic lipid accumulation
• Obesity
• Pathology
• Renal disease

Chronic Kidney Disease (CKD) is a global health problem annually affecting millions of people around the world. It is a comprehensive syndrome, and various factors may contribute to its occurrence. In this study, it was attempted to provide an accurate definition of chronic kidney disease; followed by focusing and discussing on molecular pathogenesis, novel diagnosis approaches based on biomarkers, recent effective antigens and new therapeutic procedures related to high-risk chronic kidney disease such as membranous glomerulonephritis, focal segmental glomerulosclerosis, and IgA nephropathy, which may lead to end-stage renal diseases. Additionally, a considerable number of metabolites and proteins that have previously been discovered and recommended as potential biomarkers of various CKD_s using ‘-omics-’ technologies, proteomics, and metabolomics were reviewed.

• Biomarker
• Focal segmental glomerulonephritis
• IgA nephropathy
• Membranous glomerulonephritis
• Proteomics

A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.

• differentiation
• niches
• papilla
• renal stem cells
• scattered tubular cells

• Animals
• Cell Dedifferentiation/physiology
• Epithelial Cells/cytology
• Epithelium/physiology
• Humans
• Kidney Tubules/cytology
• Regeneration/physiology
• Stem Cells/cytology

• Aged
• Apoptosis
• Biomarkers/metabolism
• Biopsy
• Diabetes Mellitus, Type 2/pathology
• Diabetes Mellitus, Type 2/urine
• Diabetic Nephropathies/metabolism
• Diabetic Nephropathies/pathology
• Female
• Humans
• Kidney Glomerulus/metabolism
• Kidney Glomerulus/ultrastructure
• Male
• Middle Aged
• Mitosis
• Podocytes/metabolism
• Podocytes/ultrastructure

• K08 HL145138 NHLBI NIH HHS

• Electron microscopy
• Focal segmental glomerulosclerosis
• immunohistochemistry CD44 and WT-1
• parietal epithelial cells
• podocytes

• atubular glomeruli
• hypoxia
• renin–angiotensin–aldosterone system
• tubuloglomerular cross talk
• tubuloglomerular feedback

• iPSCs
• kidney
• regeneration
• renal progenitor cells
• stem cells

• Mesenchymal stem cells
• amyloidosis
• light chain deposition disease
• mesangial repair
• mesangium

Podocytes are mainly involved in the regulation of glomerular filtration rate (GFR) under physiological condition. Podocyte depletion is a crucial pathological alteration in diabetic nephropathy (DN) and results in a broad spectrum of clinical syndromes such as protein urine and renal insufficiency. Recent studies indicate that depleted podocytes can be regenerated via differentiation of the parietal epithelial cells (PECs), which serve as the local progenitors of podocytes. However, the podocyte regeneration process is regulated by a complicated mechanism of cell-cell interactions and cytokine stimulations, which has been studied in a piecemeal manner rather than systematically. To address this gap, we developed a high-resolution multi-scale multi-agent mathematical model in 3D, mimicking the in situ glomerulus anatomical structure and micro-environment, to simulate the podocyte regeneration process under various cytokine perturbations in healthy and diabetic conditions. Our model showed that, treatment with pigment epithelium derived factor (PEDF) or insulin-like growth factor-1 (IGF-1) alone merely ameliorated the glomerulus injury, while co-treatment with both cytokines replenished the damaged podocyte population gradually. In addition, our model suggested that continuous administration of PEDF instead of a bolus injection sustained the regeneration process of podocytes. Part of the results has been validated by our in vivo experiments. These results indicated that amelioration of the glomerular stress by PEDF and promotion of PEC differentiation by IGF-1 are equivalently critical for podocyte regeneration. Our 3D multi-scale model represents a powerful tool for understanding the signaling regulation and guiding the design of cytokine therapies in promoting podocyte regeneration.

• diabetic nephropathy
• glomerulus
• multi-agent model
• multi-scale model
• podocyte regeneration

• CD44 staining
• Children
• Chronic kidney disease
• Focal segmental glomerulosclerosis
• Parietal epithelial cells
• Proteinuria
• Renal function

Chronic kidney disease is a prevalent condition that affects millions of people worldwide and is a major risk factor of cardiovascular morbidity and mortality. The main diseases that lead to chronic kidney disease are frequent entities as diabetes mellitus, hypertension and glomerulopathies. One of the clinical markers of kidney disease progression is proteinuria. Moreover, the histological hallmark of kidney disease is sclerosis, located both in the glomerular and in the interstitial compartments. Glomerulosclerosis underscores an irreversible lesion that is clinically accompanied by proteinuria. In this regard, proteinuria and glomerular sclerosis are linked by the cell that has been conserved phylogenetically not only to prevent the loss of proteins in the urine, but also to maintain the health of the glomerular filtration barrier: The podocyte. It can then be concluded that the link between proteinuria, kidney disease progression and chronic kidney disease is mainly related to the podocyte. What is this situation due to? The podocyte is unable to proliferate under normal conditions, and a complex molecular machinery exists to avoid its detachment and eventual loss. When the loss of podocytes in the urine, or podocyturia, is taking place and its glomerular absolute number decreased, glomerulosclerosis is the predominant histological feature in a kidney biopsy. Therefore, tissular podocyte shortage is the cause of proteinuria and chronic kidney disease. In this regard, podocyturia has been demonstrated to precede proteinuria, showing that the clinical management of proteinuria cannot be considered an early intervention. The identification of urinary podocytes could be an additional tool to be considered by nephrologists to assess the activity of glomerulopathies, for follow-up purposes and also to unravel the pathophysiology of podocyte detachment in order to tailor the therapy of glomerular diseases more appropriately.

• Podocyte
• Podocyturia
• Glomerulopathy
• Chronic kidney disease
• Proteinuria

• Maladaptive repair
• acute tubular injury
• ischemia-reperfusion
• kidney development
• transcriptional profiling
• tubular repair

Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs) has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.

• Focal segmental glomerulosclerosis
• Parietal epithelial cells
• Permeability factors
• Podocytopathy

Podocyte loss is the initial event in the development of glomerulosclerosis, the structural hallmark of progressive proteinuric nephropathies. Understanding mechanisms underlying glomerular injury is the key challenge for identifying novel therapeutic targets. In mice with protein-overload induced by bovine serum albumin (BSA), we evaluated whether the alternative pathway (AP) of complement mediated podocyte depletion and podocyte-dependent parietal epithelial cell (PEC) activation causing glomerulosclerosis. Factor H (Cfh^−/−) or factor B-deficient mice were studied in comparison with wild-type (WT) littermates. WT+BSA mice showed podocyte depletion accompanied by glomerular complement C3 and C3a deposits, PEC migration to capillary tuft, proliferation, and glomerulosclerosis. These changes were more prominent in Cfh^−/− +BSA mice. The pathogenic role of AP was documented by data that factor B deficiency preserved glomerular integrity. In protein-overload mice, PEC dysregulation was associated with upregulation of CXCR4 and GDNF/c-Ret axis. In vitro studies provided additional evidence of a direct action of C3a on proliferation and CXCR4-related migration of PECs. These effects were enhanced by podocyte-derived GDNF. In patients with proteinuric nephropathy, glomerular C3/C3a paralleled PEC activation, CXCR4 and GDNF upregulation. These results indicate that mechanistically uncontrolled AP complement activation is not dispensable for podocyte-dependent PEC activation resulting in glomerulosclerosis.

• Actin cytoskeleton
• Foot process effacement
• Nephrotic syndrome
• Podocyte
• Treatment

Kidney disease is an escalating global health problem, for which the formulation of therapeutic approaches using stem cells has received increasing research attention. The complexity of kidney anatomy and function, which includes the diversity of renal cell types, poses formidable challenges in the identification of methods to generate replacement structures. Recent work using the zebrafish has revealed their high capacity to regenerate the integral working units of the kidney, known as nephrons, following acute injury. Here, we discuss these findings and explore the ways that zebrafish can be further utilized to gain a deeper molecular appreciation of renal stem cell biology, which may uncover important clues for regenerative medicine.

• Kidney
• Renal stem cell
• Renal progenitor
• Regeneration
• Nephron
• Blood filter
• Renal corpuscle
• Tubule

• DP2 OD008470 NIH HHS

The kidney is a specialized low-regenerative organ with several different types of cellular lineages. The BrdU label-retaining cell (LRCs) approach has been used as part of a strategy to identify tissue-specific stem cells in the kidney; however, because the complementary base pairing in double-stranded DNA blocks the access of the anti-BrdU antibody to BrdU subunits, the stem cell marker expression in BrdU-labeled cells are often difficult to detect. In this study, we introduced a new cell labeling and detection method in which BrdU was replaced with 5-ethynyl-2-deoxyuridine (EdU) and examined the time-dependent dynamic changes of EdU-labeled cells and potential stem/progenitor markers in the development of kidney.

Newborn rats were intraperitoneally injected with EdU, and their kidneys were harvested respectively at different time points at 1 day, 3 days, 1 week, 2 weeks, and 6 weeks post-injection. The kidney tissues were processed for EdU and cellular markers by immunofluorescence staining.

At the early stage, LRCs labeled by EdU were 2176.0 ± 355.6 cells at day one in each renal tissue section, but dropped to 168 ± 48.4 cells by week 6. As time increased, the numbers of LRCs were differentially expressed in the renal cortex and papilla. At the postnatal day one, nearly twice as many cells in the cortex were EdU-labeled as compared to the papilla (28.6 ± 3.6% vs. 15.6 ± 3.4%, P<0.05), while there were more LRCs within the renal papilla since the postnatal week one, and at the postnatal week 6, one third as many cells in the cortex were EdU-labeled as compared to the papilla (2.5 ± 0.1% vs. 7.7 ± 2.7%, P<0.05). The long-term LRCs at 6-week time point were associated exclusively with the glomeruli in the cortex and the renal tubules in the papilla. At 6 weeks, the EdU-labeled LRCs combined with expression of CD34, RECA-1, Nestin, and Synaptopodin were discretely but widely distributed within the glomeruli; Stro-1 around the glomeruli; and α-smooth muscle actin (SMA) in arteries. Conversely, co-expression of CD34, RECA-1, and Nestin with the long term EdU-labeled LRCs was significantly lower in renal tubules (P<0.01), while Stro-1 and Synaptopodin were not detected.

Our data found that at 6-week time point, EdU-labeled LRCs existing in the glomeruli expressed undifferentiated podocyte and endothelial markers at high rates, while those in the renal tubules expressed Nestin and vascular markers at low rates. To understand the characterization and localization of these EdU-LRCs, further studies will be needed to test cell lineage tracing, clonogenicity and differentiation potency, and the contributions to the regeneration of the kidney in response to renal injury/repair.

• Animals
• Biomarkers/metabolism
• Bromodeoxyuridine/metabolism
• Cell Differentiation
• Cell Lineage
• Cell Proliferation
• Deoxyuridine/analogs & derivatives
• Deoxyuridine/metabolism
• Fluorescent Antibody Technique
• Image Processing, Computer-Assisted
• Kidney/cytology
• Kidney/metabolism
• Kinetics
• Male
• Organogenesis/physiology
• Rats
• Rats, Sprague-Dawley
• Staining and Labeling
• Stem Cells/cytology
• Stem Cells/metabolism

Reversal of diabetic nephropathy (DN) has been achieved in humans and mice, but only rarely and under special circumstances. Since progression of DN is related to podocyte loss, reversal of DN requires restoration of podocytes. Here we identified and quantified potential glomerular progenitor cells that could be a source for restored podocytes. DN was identified in 31 human renal biopsy cases and separated into morphologically early or advanced lesions. Markers of podocytes (WT-1, p57), parietal epithelial cells (claudin-1) and cell proliferation (Ki-67) were identified by immunohistochemistry. Podocyte density was progressively reduced with DN. Cells marking as podocytes (p57) were present infrequently on Bowman's capsule in controls, but significantly increased in histologically early DN. Ki-67 expressing cells were identified on the glomerular tuft and Bowman's capsule in DN, but rarely in controls. Cells marking as PECs were present on the glomerular tuft, particularly in morphologically advanced DN. These findings show evidence of phenotypic plasticity in podocyte and PEC populations and are consistent with studies in the BTBR ob/ob murine model in which reversibility of DN occurs with podocytes potentially regenerating from PEC precursors. Thus, our findings support, but do not prove, that podocytes may regenerate from PEC progenitors in human DN. If so, progression of DN may represent a modifiable net balance between podocyte loss and regeneration.

Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration.

• Stem cell
• Label-retaining cells
• rKS56
• SP cells
• CD24
• CD133
• Sca-1
• Induced pluripotent stem
• ES cell

• glomerulonephritis
• glomerulosclerosis
• kidney
• mutation
• next generation
• podocytes

• development
• glomerulus
• kidney
• podocyte
• regeneration
• renal corpuscle
• zebrafish

• Retinoic acid
• glomerular regeneration
• kidney