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Nature Biotechnology Nov 2015Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regeneration, disease modeling and drug screening. We report an efficient,...
Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regeneration, disease modeling and drug screening. We report an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2+ SALL1+ WT1+ PAX2+ NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8+ LHX1+ renal vesicles that self-organize into nephron structures. In both two- and three-dimensional culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidney development and toxicity.
Topics: Biomedical Research; Cell Culture Techniques; Cell Differentiation; Humans; Kidney; Models, Biological; Nephrons; Organoids; Pluripotent Stem Cells; Tissue Culture Techniques
PubMed: 26458176
DOI: 10.1038/nbt.3392 -
American Journal of Physiology. Renal... May 2019Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration.... (Review)
Review
Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration. Each mechanism generates a self-sustained oscillation, the mechanisms interact, and the oscillations synchronize. The synchronization generates a bimodal electrical signal in the arteriolar wall that propagates retrograde to a vascular node, where it meets similar electrical signals from other nephrons. Each signal carries information about the time-dependent behavior of the regulatory ensemble. The converging signals support synchronization of the nephrons participating in the information exchange, and the synchronization can lead to formation of nephron clusters. We review the experimental evidence and the theoretical implications of these interactions and consider additional interactions that can limit the size of nephron clusters. The architecture of the arterial tree figures prominently in these interactions.
Topics: Animals; Arterioles; Blood Flow Velocity; Glomerular Filtration Rate; Homeostasis; Humans; Kidney Glomerulus; Kidney Tubules; Models, Biological; Renal Circulation; Signal Transduction
PubMed: 30759020
DOI: 10.1152/ajprenal.00484.2018 -
Pediatric Nephrology (Berlin, Germany) Apr 2014The nephron is the functional unit that executes the homeostatic roles of the kidney in vertebrates. Critical to this function is the physical arrangement of the... (Review)
Review
The nephron is the functional unit that executes the homeostatic roles of the kidney in vertebrates. Critical to this function is the physical arrangement of the glomerular blood filter attached to a tubular epithelium that is subdivided into specialized proximal and distal segments. During embryogenesis, nephron progenitors undergo a mesenchymal-epithelial transition (MET) and adopt different segment-specific cell fates along the proximo-distal axis of the nephron. The molecular basis of how these segments arise remains largely unknown. Recent studies using the zebrafish have identified the Hnf1beta transcription factor (Hnf1b) as a major regulator of tubular segmentation. In Hnf1b-deficient zebrafish embryos, nephron progenitors fail to adopt the proximo-distal segmentation pattern of the nephron, yet still undergo MET. This observation suggests that the functional segmentation of renal tubular epithelial cells is independent of pathways that induce their epithelialization. Here we review this new role of Hnf1b for nephron segmentation during zebrafish and mouse kidney development.
Topics: Animals; Hepatocyte Nuclear Factor 1-beta; Humans; Nephrons; Organogenesis; Zebrafish Proteins
PubMed: 24190171
DOI: 10.1007/s00467-013-2662-x -
Anatomical Record (Hoboken, N.J. : 2007) Oct 2020Recent studies have reported that total nephron number varies widely in human kidneys and some racial groups with low nephron number have a higher incidence of... (Review)
Review
Recent studies have reported that total nephron number varies widely in human kidneys and some racial groups with low nephron number have a higher incidence of hypertension and kidney disease. Importantly, nephrogenesis normally reaches completion at about 34-36 weeks gestation, with no new nephrons formed for the lifetime in humans after this time. Although the loss of glomeruli varies among individuals due to aging, blood pressure, or additional inducers of kidney injury, much of the variation in nephron number is nowadays thought to be present at birth. According to the hyperfiltration hypothesis, this subsequent nephron loss results in compensatory hyperfiltration and/or hypertension of remaining glomeruli, thereby contributing to increased susceptibility to systemic hypertension. However, recent studies have suggested that the association between a low nephron number and systemic hypertension is not a universal finding. In most studies to date, nephron counts were performed on kidneys obtained at autopsy. Several recent studies have attempted to estimate nephron number in living human subjects, but further work is required to obtain accurate and precise estimates of nephron number using these noninvasive methods. Longitudinal studies in living humans have the potential to reveal associations between nephron number and hypertension/renal pathology.
Topics: Blood Pressure; Humans; Hypertension; Kidney; Kidney Glomerulus; Nephrons
PubMed: 31729838
DOI: 10.1002/ar.24302 -
Advances in Physiology Education Jun 2018The purpose of this study is to see whether a large drawing of a nephron helped medical students in self-directed learning groups learn renal physiology, histology, and...
The purpose of this study is to see whether a large drawing of a nephron helped medical students in self-directed learning groups learn renal physiology, histology, and pharmacology before discussing clinical cases. The end points were the grades on the renal examination and a student survey. The classes in the fall of 2014 and 2015 used the drawing, but not those of 2012 and 2013. The Charles E. Schmidt College of Medicine at Florida Atlantic University is a newly formed Florida medical school, which enrolled its first class in the fall of 2011. The school relies on self-directed problem-based learning in year 1 and changes over to a case inquiry method in the latter part of year 1 and throughout year 2. At the start of the renal course, each student group received a poster of a nephron with the objective of learning the cell functions of the different nephron parts. During the first year of using the drawing, there was no improvement in grades. After a student suggested adjustment to the drawing, there was a statistically significant difference in the total test score in the second year ( P < 0.001). An unexpected finding was lower grades in all 4 yr in the area of acid-base balance and electrolytes compared with the other four areas tested. In the survey, the students found the drawing useful.
Topics: Education, Medical; Educational Measurement; Female; Histology; Humans; Kidney; Male; Nephrons; Pharmacology; Physiology; Problem-Based Learning; Retrospective Studies; Students, Medical; Teaching; Young Adult
PubMed: 29616568
DOI: 10.1152/advan.00022.2017 -
Physiological Genomics Mar 2017The kidneys play a vital role in the excretion of waste products and the regulation of electrolytes, maintenance of acid-base balance, regulation of blood pressure, and... (Review)
Review
The kidneys play a vital role in the excretion of waste products and the regulation of electrolytes, maintenance of acid-base balance, regulation of blood pressure, and production of several hormones. Any alteration in the structure of the nephron (basic functional unit of the kidney) can have a major impact on the kidney's ability to work efficiently. Progressive decline in kidney function can lead to serious illness and ultimately death if not treated by dialysis or transplantation. While there have been numerous studies that implicate lower nephron numbers as being an important factor in influencing susceptibility to developing hypertension and chronic kidney disease, a direct association has been difficult to establish because of three main limitations: ) the large variation in nephron number observed in the human population; ) no established reliable noninvasive methods to determine nephron complement; and ) to date, nephron measurements have been done after death, which doesn't adequately account for potential loss of nephrons with age or disease. In this review, we will provide an overview of kidney structure/function, discuss the current literature for both humans and other species linking nephron deficiency and cardio-renal complications, as well as describe the major molecular signaling factors involved in nephrogenesis that modulate variation in nephron number. As more detailed knowledge about the molecular determinants of nephron development and the role of nephron endowment in the cardio-renal system is obtained, it will hopefully provide clinicians the ability to accurately identify people at risk to develop CKD/hypertension and lead to a shift in patient care from disease treatment to prevention.
Topics: Animals; Disease Models, Animal; Humans; Hypertension; Models, Biological; Nephrons; Organogenesis; Renal Insufficiency, Chronic
PubMed: 28130427
DOI: 10.1152/physiolgenomics.00098.2016 -
Seminars in Cell & Developmental Biology Dec 2014The functional unit of the mammalian metanephric kidney is the nephron: a complex tubular structure dedicated to blood filtration and maintenance of several important... (Review)
Review
The functional unit of the mammalian metanephric kidney is the nephron: a complex tubular structure dedicated to blood filtration and maintenance of several important physiological functions. Nephrons are assembled from a nephron-restricted pool of mesenchymal progenitors over an extensive developmental period that is completed prior to (human), or shortly after (mouse), birth. An appropriate balance in the expansion and commitment of nephron progenitors to nephron formation is essential for normal kidney function. Too few nephrons increase risk of kidney disease later in life while the failure of normal progenitor differentiation in Wilm's tumor patients leads to massive growth of a nephroblast population often necessitating surgical removal of the kidney. An inductive process within the metanephric mesenchyme leads to the formation of a pretubular aggregate which transitions into an epithelial renal vesicle: the precursor for nephron assembly. Growth, morphogenesis and patterning transform this simple cyst-like structure into a highly elongated mature nephron with distinct cell types positioned along a proximal (glomerular) to distal (connecting segment) axis of functional organization. This review discusses our current understanding of the specification, maintenance and commitment of nephron progenitors, and the regulatory processes that transform the renal vesicle into a nephron.
Topics: Animals; Cell Differentiation; Gene Expression Regulation, Developmental; Humans; Mesenchymal Stem Cells; Mice; Nephrons; Organogenesis; Receptors, Notch; Wilms Tumor; Wnt Proteins; Wnt Signaling Pathway
PubMed: 25194660
DOI: 10.1016/j.semcdb.2014.08.014 -
F1000Research 2019Regeneration of a functional kidney from pluripotent stem cells (PSCs) is challenging because of its complex structure. Kidneys are derived from embryonic metanephros,... (Review)
Review
Regeneration of a functional kidney from pluripotent stem cells (PSCs) is challenging because of its complex structure. Kidneys are derived from embryonic metanephros, which are composed of three progenitor cells: nephron progenitors, ureteric bud, and stromal progenitors. Nephron progenitors and ureteric bud have been induced successfully from PSCs as a result of the understanding of their detailed developmental process through cell-lineage tracing analysis. Moreover, these induced progenitors can be used to reconstruct the three-dimensional (3D) structure of kidneys , including glomeruli with podocytes, renal tubules, and the branching ureters. Induction of the remaining renal progenitors (that is, stromal progenitors from PSCs and the further maturation of reconstructed kidneys) needs to be studied extensively to regenerate functional and sophisticated kidneys from PSCs. In addition to the proper induction of renal progenitors, new bioengineering methods such as decellularization and 3D bioprinting and the recent advancements in the regeneration of kidneys in other species are promising leads for regenerating the complex spatial arrangement of kidneys, including the vascular network and urinary excretion pathway in humans.
Topics: Cell Differentiation; Humans; Kidney; Nephrons; Regeneration; Stem Cells; Tissue Engineering
PubMed: 30828435
DOI: 10.12688/f1000research.17127.1 -
Current Opinion in Nephrology and... Nov 2019Many studies have suggested low nephron endowment at birth contributes to the risk of developing hypertension and chronic kidney disease (CKD) later in life. Loss of... (Review)
Review
PURPOSE OF REVIEW
Many studies have suggested low nephron endowment at birth contributes to the risk of developing hypertension and chronic kidney disease (CKD) later in life. Loss of nephrons with age and disease is largely a subclinical process. New technologies are needed to count nephrons as glomerular filtration rate (GFR) is a poor surrogate for nephron number.
RECENT FINDINGS
Cortical volume, glomerular density, and percent globally sclerotic glomeruli are imperfect surrogates for nephron number. The disector-fractionator method is the most accurate method to count nephrons but is limited to autopsy settings. Glomerular density combined with kidney imaging and ultrafiltration coefficient-based methods require a kidney biopsy, and have been applied in living humans (kidney donors). Low nephron number predicts a higher postdonation urine albumin. Contrast-enhanced MRI has detected glomeruli without a biopsy, but so far, not in living humans.
SUMMARY
Currently, there is no accurate and well tolerated method for determining nephron number in living humans. A clinically useful method may allow GFR to be replaced by its more relevant determinants: nephron number and single nephron GFR. This could revolutionize nephrology by separating the measurement of chronic disease (nephron loss) from more reversible hemodynamic effects (nephron hyperfiltration/hypofiltration).
Topics: Biopsy; Glomerular Filtration Rate; Humans; Kidney; Kidney Glomerulus; Magnetic Resonance Imaging; Nephrons
PubMed: 31433316
DOI: 10.1097/MNH.0000000000000540 -
Kidney360 May 2021Single-nephron dynamics in progressive IgA nephropathy (IgAN) have not been studied. We applied novel methodology to explore single-nephron parameters in IgAN.
BACKGROUND
Single-nephron dynamics in progressive IgA nephropathy (IgAN) have not been studied. We applied novel methodology to explore single-nephron parameters in IgAN.
METHODS
Nonglobally sclerotic glomeruli (NSG) and globally sclerotic glomeruli (GSG) per kidney were estimated using cortical volume assessment unenhanced computed tomography and biopsy-based stereology. Estimated single-nephron GFR (eSNGFR) and single-nephron urine protein excretion (SNUPE) were calculated by dividing eGFR and UPE by the number of NSG. Associations with CKD stage and clinicopathologic findings were cross-sectionally investigated.
RESULTS
This study included 245 patients with IgAN (mean age 43 years, 62% male, 45% on renin-angiotensin aldosterone system [RAAS] inhibitors prebiopsy) evaluated at kidney biopsy. CKD stages were 10% CKD1, 43% CKD2, 19% CKD3a, 14% CKD3b, and 14% CKD4-5. With advancing CKD stage, NSG decreased from mean 992,000 to 300,000 per kidney, whereas GSG increased from median 64,000 to 202,000 per kidney. In multivariable models, advancing CKD stage associated with lower numbers of NSG, higher numbers of GSG, and lower numbers of GSG + NSG, indicating potential resorption of sclerosed glomeruli. In contrast to the higher mean glomerular volume and markedly elevated SNUPE in advanced CKD, the eSNGFR was largely unaffected by CKD stage. Lower SNGFR associated with Oxford scores for endocapillary hypercellularity and crescents, whereas higher SNUPE associated with segmental glomerulosclerosis and tubulointerstitial scarring.
CONCLUSIONS
SNUPE emerged as a sensitive biomarker of advancing IgAN. The failure of eSNGFR to increase in response to reduced number of functioning nephrons suggests limited capacity for compensatory hyperfiltration by diseased glomeruli with intrinsic lesions.
Topics: Adult; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Kidney; Kidney Glomerulus; Male; Nephrons
PubMed: 35373063
DOI: 10.34067/KID.0006972020