scholarly journals Pax-2 controls multiple steps of urogenital development

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4057-4065 ◽  
Author(s):  
M. Torres ◽  
E. Gomez-Pardo ◽  
G.R. Dressler ◽  
P. Gruss
Keyword(s):  
Kidney Development ◽  
Kidney Diseases ◽  
System Development ◽  
Collecting Duct ◽  
Early Embryo ◽  
Urogenital System ◽  
Newborn Mice ◽  
Intermediate Mesoderm ◽  
Mouse Mutants ◽  
Urogenital Development

Urogenital system development in mammals requires the coordinated differentiation of two distinct tissues, the ductal epithelium and the nephrogenic mesenchyme, both derived from the intermediate mesoderm of the early embryo. The former give rise to the genital tracts, ureters and kidney collecting duct system, whereas mesenchymal components undergo epithelial transformation to form nephrons in both the mesonephric (embryonic) and metanephric (definitive) kidney. Pax-2 is a transcriptional regulator of the paired-box family and is widely expressed during the development of both ductal and mesenchymal components of the urogenital system. We report here that Pax-2 homozygous mutant newborn mice lack kidneys, ureters and genital tracts. We attribute these defects to dysgenesis of both ductal and mesenchymal components of the developing urogenital system. The Wolffian and Mullerian ducts, precursors of male and female genital tracts, respectively, develop only partially and degenerate during embryogenesis. The ureters, inducers of the metanephros are absent and therefore kidney development does not take place. Mesenchyme of the nephrogenic cord fails to undergo epithelial transformation and is not able to form tubules in the mesonephros. In addition, we show that the expression of specific markers for each of these components is de-regulated in Pax-2 mutants. These data show that Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases.

scholarly journals iPSC technology-based regenerative medicine for kidney diseases

2021 ◽  
Author(s):  
Kenji Osafune
Keyword(s):  
Regenerative Medicine ◽  
Cell Therapy ◽  
Kidney Development ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Current Status ◽  
Renal Tubules ◽  
Discovery Research ◽  
Drug Discovery Research

AbstractWith few curative treatments for kidney diseases, increasing attention has been paid to regenerative medicine as a new therapeutic option. Recent progress in kidney regeneration using human-induced pluripotent stem cells (hiPSCs) is noteworthy. Based on the knowledge of kidney development, the directed differentiation of hiPSCs into two embryonic kidney progenitors, nephron progenitor cells (NPCs) and ureteric bud (UB), has been established, enabling the generation of nephron and collecting duct organoids. Furthermore, human kidney tissues can be generated from these hiPSC-derived progenitors, in which NPC-derived glomeruli and renal tubules and UB-derived collecting ducts are interconnected. The induced kidney tissues are further vascularized when transplanted into immunodeficient mice. In addition to the kidney reconstruction for use in transplantation, it has been demonstrated that cell therapy using hiPSC-derived NPCs ameliorates acute kidney injury (AKI) in mice. Disease modeling and drug discovery research using disease-specific hiPSCs has also been vigorously conducted for intractable kidney disorders, such as autosomal dominant polycystic kidney disease (ADPKD). In an attempt to address the complications associated with kidney diseases, hiPSC-derived erythropoietin (EPO)-producing cells were successfully generated to discover drugs and develop cell therapy for renal anemia. This review summarizes the current status and future perspectives of developmental biology of kidney and iPSC technology-based regenerative medicine for kidney diseases.

The surface ectoderm is essential for nephric duct formation in intermediate mesoderm

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1103-1108 ◽  
Author(s):  
T. Obara-Ishihara ◽  
J. Kuhlman ◽  
L. Niswander ◽  
D. Herzlinger
Keyword(s):  
Mrna Expression ◽  
Kidney Development ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Surface Ectoderm ◽  
Intermediate Mesoderm ◽  
Coated Bead ◽  
Urogenital Development ◽  
High Level ◽  
Lateral Mesoderm

The nephric duct is the first epithelial tubule to differentiate from intermediate mesoderm that is essential for all further urogenital development. In this study we identify the domain of intermediate mesoderm that gives rise to the nephric duct and demonstrate that the surface ectoderm is required for its differentiation. Removal of the surface ectoderm resulted in decreased levels of Sim-1 and Pax-2 mRNA expression in mesenchymal nephric duct progenitors, and caused inhibition of nephric duct formation and subsequent kidney development. The surface ectoderm expresses BMP-4 and we show that it is required for the maintenance of high-level BMP-4 expression in lateral plate mesoderm. Addition of a BMP-4-coated bead to embryos lacking the surface ectoderm restored normal levels of Sim-1 and Pax-2 mRNA expression in nephric duct progenitors, nephric duct formation and the initiation of nephrogenesis. Thus, BMP-4 signaling can substitute for the surface ectoderm in supporting nephric duct morphogenesis. Collectively, these data suggest that inductive interactions between the surface ectoderm, lateral mesoderm and intermediate mesoderm are essential for nephric duct formation and the initiation of urogenital development.

scholarly journals Kidney Organoids and Tubuloids

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1326 ◽  
Author(s):  
Fjodor A. Yousef Yengej ◽  
Jitske Jansen ◽  
Maarten B. Rookmaaker ◽  
Marianne C. Verhaar ◽  
Hans Clevers
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Kidney Development ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Metanephric Mesenchyme ◽  
Kidney Organoids

In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine.

scholarly journals Expression of Acsm2, a kidney-specific gene, parallels the function and maturation of proximal tubular cells

2020 ◽  
Vol 319 (4) ◽  
pp. F603-F611
Author(s):  
Hirofumi Watanabe ◽  
Robert L. Paxton ◽  
Matthew R. Tolerico ◽  
Vidya K. Nagalakshmi ◽  
Shinji Tanaka ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Kidney Development ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Specific Gene ◽  
Proximal Tubular Cells ◽  
Newborn Mice ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
High Level

The acyl-CoA synthetase medium-chain family member 2 ( Acsm2) gene was first identified and cloned by our group as a kidney-specific “ KS” gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the Acsm2 gene was expressed specifically and at a high level in normal adult kidneys. Expression of Acsm2 in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that Acsm2 was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the Acsm2 gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of Acsm2 in the proximal tubules was significantly decreased. In human samples, the expression pattern of ACSM2A, a homolog of mouse Acsm2, was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of Acsm2 parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that Acms2 may serve as a novel marker of proximal tubular injury and/or dysfunction.

The vasoconstrictor endothelin system involvement in chronic kidney diseases pathogenesis is now the most often employed treatment method

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Blood Pressure ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Treatment Method ◽  
Chronic Kidney Diseases ◽  
System Involvement ◽  
Duct Cells ◽  
Vasa Recta ◽  
Etb Receptor ◽  
Collecting Duct Cells

Over 30,000 publications have been published about the vasoconstrictor endothelin-1, which was identified by Yanagisawa and co-workers in 1988. While the evidence is quite compelling, scientists can only speculate on how the endothelin (ET) system affects blood pressure and renal function at this time. ET system involvement in chronic kidney diseases (CKD) pathogenesis is now the most often employed treatment method. ET1, ET2, and ET3 are all members of the endothelin family. Endothelium, renal, and smooth muscle cells all generate ET-1, a significant isoform found in both cardiovascular and renal systems.Kidney cells act on, and contain, ET-1. The ETA receptor is found in the brain and medulla, but not in the vasa recta or glomeruli. Epithelial and endothelial cells contain the ETB receptor, which is most prominent in collecting duct cells. 3 In several experiments, ET-1 has been established to be largely a preglomerular vasoconstrictor. Mesangial proliferation, contraction, and collagen production are regulated by ET-1 and ETB receptors in podocytes. The epithelium in the collecting duct cells in the medulla is important in controlling Na excretion and BP. Without the ET-1 gene, the mice have hypertension and reduced natriuresis in response to salt loading. Et-1, ETB receptor, and hypertension are shown in mice that have lost the ETB receptor gene. There is no correlation between blood pressure regulation and natriuresis.Combined disruption of the ETA and ETB receptors has greater effects on blood pressure and Na reabsorption than when ETB receptor activity is missing. It appears that the ETB receptor doesn't work until ETB is present. Collecting duct-derived ET receptors reduces the transport of sodium. Src kinase and MAPK1/2 decrease epidermal Na channel (ENaC) function, decreasing water and salt reabsorption. Moreover, inner medullary collecting duct cells and vasa recta-bearing cells will release NO, which decreases sodium transport.

Sulphated proteoglycan is required for collecting duct growth and branching but not nephron formation during kidney development

Development ◽  
1995 ◽  
Vol 121 (5) ◽  
pp. 1507-1517 ◽  
Author(s):  
J. Davies ◽  
M. Lyon ◽  
J. Gallagher ◽  
D. Garrod
Keyword(s):  
Kidney Development ◽  
Collecting Duct ◽  
Sodium Chlorate ◽  
Ureteric Bud ◽  
Nephron Differentiation ◽  
Bud Growth ◽  
Nephron Development ◽  
Sulphated Glycosaminoglycans ◽  
Sulphated Proteoglycan ◽  
Hepatocyte Growth

Kidney epithelia have separate origins; collecting ducts develop by ureteric bud growth and arborisation, nephrons by induced mesenchyme-epithelium transition. Both express sulphated glycosaminoglycans (GAGs) which are strikingly upregulated during nephron differentiation. However, sodium chlorate, an inhibitor of GAG sulphation, and the GAG-degrading enzymes heparitinase plus chondroitinase, did not prevent nephron development. In contrast, ureteric bud growth and branching were reversibly inhibited by the above reagents, the inhibition correlating quantitatively with sulphated GAG deprivation caused by a range of chlorate concentrations. Growth and branching could be independently restored during GAG deprivation by hepatocyte growth factor and phorbol-12-myristate acetate (PMA) respectively. Together these signalling effectors stimulated both branch initiation and growth. Thus growth and morphogenesis of ureteric bud involve distinct signalling pathways both regulated by GAGs.

Abnormal postpartum renal development and cystogenesis in the bcl-2 (-/-) mouse

1996 ◽  
Vol 271 (1) ◽  
pp. F184-F193 ◽  
Author(s):  
C. M. Sorenson ◽  
B. J. Padanilam ◽  
M. R. Hammerman
Keyword(s):  
Cellular Proliferation ◽  
Kidney Development ◽  
Apoptotic Cell ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Renal Development ◽  
Thick Ascending Limb ◽  
Renal Hypoplasia ◽  
Cellular Origin ◽  
Bax Protein

Mice deficient for B cell leukemia/lymphoma gene 2 [bcl-2(-/-) mice] manifest congenital renal hypoplasia and develop multicystic kidney disease and renal failure postnatally. To characterize postpartum renal development, to identify the cellular origin of the cysts, and to provide insight into the role that bcl-2 deficiency plays in the cystogenic process, we examined the morphology of kidneys from bcl-2 (-/-) mice and wild-type littermates [bcl-2 (+/+)] from birth (P0) to postpartum day 28 (P28), determined whether abnormalities of cellular proliferation and apoptosis accompany cyst development, and characterized expression of the bcl-2-related protein, bax. Between P0 and P7, kidneys from bcl-2 (-/-) and bcl-2 (+/+) mice undergo a comparable increase in weight and have similar histological appearances. However, during the next 2 wk of life, weight gain in kidneys from bcl-2 (-/-) mice is reduced compared with that in kidneys from bcl-2 (+/+) animals, and cysts develop in tubules with staining characteristics of proximal tubule, distal tubule/medullary thick ascending limb of Henle's loop, and collecting duct. Unaffected glomeruli and proximal tubules in kidneys of bcl-2 (-/-) mice undergo compensatory growth. Cystogenesis is accompanied by enhanced incorporation of 5-bromo-2'-deoxyuridine in cells within cortex and medulla and apoptosis of cells within cysts and in the renal interstitium. Bax protein is expressed in the distal tubule in kidneys of bcl-2 (+/+) and bcl-2 (-/-) mice and in some, but not all cysts. We conclude that abnormal regulation of DNA synthesis and apoptosis accompany cystogenesis in bcl-2 (-/-) mice during postpartum kidney development. Continued expression of bax could enhance apoptotic cell death.0

Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: implications for terminal nephron differentiation

2005 ◽  
Vol 288 (5) ◽  
pp. F899-F909 ◽  
Author(s):  
Zubaida Saifudeen ◽  
Susana Dipp ◽  
Hao Fan ◽  
Samir S. El-Dahr
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Binding ◽  
Spatial Organization ◽  
Kidney Development ◽  
Collecting Duct ◽  
Proximal Promoter ◽  
Bradykinin B2 Receptor ◽  
Nephron Differentiation ◽  
Terminal Nephron

Despite a wealth of knowledge regarding the early steps of epithelial differentiation, little is known about the mechanisms responsible for terminal nephron differentiation. The bradykinin B2 receptor (B2R) regulates renal function and integrity, and its expression is induced during terminal nephron differentiation. This study investigates the transcriptional regulation of the B2R during kidney development. The rat B2R 5′-flanking region has a highly conserved cis-acting enhancer in the proximal promoter consisting of contiguous binding sites for the transcription factors cAMP response element binding protein (CREB), p53, and Krüppel-like factor (KLF-4). The B2R enhancer drives reporter gene expression in inner medullary collecting duct-3 cells but is considerably weaker in other cell types. Site-directed mutagenesis and expression of dominant negative mutants demonstrated the requirement of CREB DNA binding and Ser-133 phosphorylation for optimal enhancer function. Moreover, helical phasing experiments showed that disruption of the spatial organization of the enhancer inhibits B2R promoter activity. Several lines of evidence indicate that cooperative interactions among the three transcription factors occur in vivo during terminal nephron differentiation: 1) CREB, p53, and KLF-4 are coexpressed in B2R-positive differentiating cells; 2) the maturational expression of B2R correlates with CREB/p53/KLF-4 DNA-binding activity; 3) assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation; and 4) CREB and p53 occupancy of the B2R enhancer is cooperative. These results demonstrate that combinatorial interactions among the transcription factors, CREB, p53, and KLF-4, and the coactivator CBP, may be critical for the regulation of B2R gene expression during terminal nephron differentiation.

scholarly journals Single-cell RNA sequencing reveals differential cell cycle activity in key cell populations during nephrogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abha S. Bais ◽  
Débora M. Cerqueira ◽  
Andrew Clugston ◽  
Andrew J. Bodnar ◽  
Jacqueline Ho ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Collecting Duct ◽  
Cell Types ◽  
Nephron Progenitors ◽  
Developing Kidney ◽  
Distal Tubules ◽  
Cycle Regulation

AbstractThe kidney is a complex organ composed of more than 30 terminally differentiated cell types that all are required to perform its numerous homeostatic functions. Defects in kidney development are a significant cause of chronic kidney disease in children, which can lead to kidney failure that can only be treated by transplant or dialysis. A better understanding of molecular mechanisms that drive kidney development is important for designing strategies to enhance renal repair and regeneration. In this study, we profiled gene expression in the developing mouse kidney at embryonic day 14.5 at single-cell resolution. Consistent with previous studies, clusters with distinct transcriptional signatures clearly identify major compartments and cell types of the developing kidney. Cell cycle activity distinguishes between the “primed” and “self-renewing” sub-populations of nephron progenitors, with increased expression of the cell cycle-related genes Birc5, Cdca3, Smc2 and Smc4 in “primed” nephron progenitors. In addition, augmented expression of cell cycle related genes Birc5, Cks2, Ccnb1, Ccnd1 and Tuba1a/b was detected in immature distal tubules, suggesting cell cycle regulation may be required for early events of nephron patterning and tubular fusion between the distal nephron and collecting duct epithelia.

scholarly journals Calcium-permeable ion channels in the kidney

2016 ◽  
Vol 310 (11) ◽  
pp. F1157-F1167 ◽  
Author(s):  
Yiming Zhou ◽  
Anna Greka
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Transient Receptor Potential ◽  
Kidney Development ◽  
Kidney Diseases ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Cellular Functions ◽  
Potential Channels ◽  
Transient Receptor

Calcium ions (Ca2+) are crucial for a variety of cellular functions. The extracellular and intracellular Ca2+ concentrations are thus tightly regulated to maintain Ca2+ homeostasis. The kidney, one of the major organs of the excretory system, regulates Ca2+ homeostasis by filtration and reabsorption. Approximately 60% of the Ca2+ in plasma is filtered, and 99% of that is reabsorbed by the kidney tubules. Ca2+ is also a critical signaling molecule in kidney development, in all kidney cellular functions, and in the emergence of kidney diseases. Recently, studies using genetic and molecular biological approaches have identified several Ca2+-permeable ion channel families as important regulators of Ca2+ homeostasis in kidney. These ion channel families include transient receptor potential channels (TRP), voltage-gated calcium channels, and others. In this review, we provide a brief and systematic summary of the expression, function, and pathological contribution for each of these Ca2+-permeable ion channels. Moreover, we discuss their potential as future therapeutic targets.

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