Complex dynamics in a fractional order nephron pressure and flow regulation model.

Cardiovascular diseases can be attributed to irregular blood pressure, which may be caused by malfunctioning kidneys that regulate blood pressure. Research has identified complex oscillations in the mechanisms used by the kidney to regulate blood pressure. This study uses established physiological knowledge and earlier autoregulation models to derive a fractional order nephron autoregulation model. The dynamical behaviour of the model is analyzed using bifurcation plots, revealing periodic oscillations, chaotic regions, and multistability. A lattice array of the model is used to study collective behaviour and demonstrates the presence of chimeras in the network. A ring network of the fractional order model is also considered, and a diffusion coupling strength is adopted. A basin of synchronization is derived, considering coupling strength, fractional order or number of neighbours as parameters, and measuring the strength of incoherence. Overall, the study provides valuable insights into the complex dynamics of the nephron autoregulation model and its potential implications for cardiovascular diseases.

Stromal Transcription Factor 21 Regulates Development of the Renal Stroma via Interaction with Wnt/ß-Catenin Signaling.

Background: Kidney formation requires coordinated interactions between multiple cell types. Input from the interstitial progenitor cells is implicated in multiple aspects of kidney development. We previously reported that transcription factor 21 (Tcf21) is required for ureteric bud branching. Here, we show that Tcf21 in Foxd1+ interstitial progenitors regulates stromal formation and differentiation via interaction with ß-catenin. Methods: We utilized the Foxd1Cre;Tcf21f/f murine kidney for morphologic analysis. We used the murine clonal mesenchymal cell lines MK3/M15 to study Tcf21 interaction with Wnt/ß-catenin. Results: Absence of Tcf21 from Foxd1+ stromal progenitors caused a decrease in stromal cell proliferation, leading to marked reduction of the medullary stromal space. Lack of Tcf21 in the Foxd1+ stromal cells also led to defective differentiation of interstitial cells to smooth-muscle cells, perivascular pericytes, and mesangial cells. Foxd1Cre;Tcf21f/f kidney showed an abnormal pattern of the renal vascular tree. The stroma of Foxd1Cre;Tcf21f/f kidney demonstrated marked reduction in ß-catenin protein expression compared with wild type. Tcf21 was bound to ß-catenin both upon ß-catenin stabilization and at basal state as demonstrated by immunoprecipitation in vitro. In MK3/M15 metanephric mesenchymal cells, Tcf21 enhanced TCF/LEF promoter activity upon ß-catenin stabilization, whereas DNA-binding deficient mutated Tcf21 did not enhance TCF/LEF promoter activity. Kidney explants of Foxd1Cre;Tcf21f/f showed low mRNA expression of stromal Wnt target genes. Treatment of the explants with CHIR, a Wnt ligand mimetic, restored Wnt target gene expression. Here, we also corroborated previous evidence that normal development of the kidney stroma is required for normal development of the Six2+ nephron progenitor cells, loop of Henle, and the collecting ducts. Conclusions: These findings suggest that stromal Tcf21 facilitates medullary stroma development by enhancing Wnt/ß-catenin signaling and promotes stromal cell proliferation and differentiation. Stromal Tcf21 is also required for the development of the adjacent nephron epithelia.

Synchronization in renal microcirculation unveiled with high-resolution blood flow imaging.

Internephron interaction is fundamental for kidney function. Earlier studies have shown that nephrons signal to each other, synchronize over short distances, and potentially form large synchronized clusters. Such clusters would play an important role in renal autoregulation, but due to the technological limitations, their presence is yet to be confirmed. In the present study, we introduce an approach for high-resolution laser speckle imaging of renal blood flow and apply it to estimate the frequency and phase differences in rat kidney microcirculation under different conditions. The analysis unveiled the spatial and temporal evolution of synchronized blood flow clusters of various sizes, including the formation of large (>90 vessels) and long-lived clusters (>10 periods) locked at the frequency of the tubular glomerular feedback mechanism. Administration of vasoactive agents caused significant changes in the synchronization patterns and, thus, in nephrons' co-operative dynamics. Specifically, infusion of vasoconstrictor angiotensin II promoted stronger synchronization, while acetylcholine caused complete desynchronization. The results confirm the presence of the local synchronization in the renal microcirculatory blood flow and that it changes depending on the condition of the vascular network and the blood pressure, which will have further implications for the role of such synchronization in pathologies development.

Pregnancy and severely reduced renal mass: A stress model showing renal hyperfiltration.

Pregnancy may increase signs of renovascular stress. We compared pregnant sham operated (S) and 5/6 nephrectomy (NX) rats to examine the effect of pregnancy on reduced nephron number. Blood pressure (BP), heart rate (HR), body weight (BW), food/water intake, serum creatinine (Cr), urinalyses were assessed weekly, and end pregnancy renal histology examined. NX showed decreased BW, elevated BP and Cr, and proteinuria. Histology revealed increased glomerular volume, increased tubular diameter and interstitial inflammation and fibrosis. This pilot shows that a pregnant 5/6th nephrectomy rat is a reliable model in which to evaluate renovascular stress with reduced nephrons.

Nephron mass determines the excretion rate of urinary extracellular vesicles.

Urinary extracellular vesicles (uEVs) are emerging as non-invasive biomarkers for various kidney diseases, but it is unknown how differences in nephron mass impact uEV excretion. To address this, uEV excretion was measured before and after human kidney donor nephrectomy and rat nephrectomy. In male and female donors, uEVs were quantified in cell-free spot and 24-h urine samples using nanoparticle tracking analysis (NTA), EVQuant, and CD9-time-resolved fluorescence immunoassay. Female donors had significantly lower total kidney volume (TKV) and excreted 49% fewer uEVs than male donors. uEV excretion correlated positively with estimated glomerular filtration rate (eGFR), creatinine clearance, and TKV (R's between 0.6 and 0.7). uEV excretion rate could also be predicted from spot urines after multiplying spot uEV/creatinine by 24-h urine creatinine. Donor nephrectomy reduced eGFR by 36% ± 10%, but the excretion of uEVs by only 16% (CD9+ uEVs -37%, CD9- uEVs no decrease). Donor nephrectomy increased the podocyte marker WT-1 and the proximal tubule markers NHE3, NaPi-IIa, and cubilin in uEVs two- to four-fold when correcting for the nephrectomy. In rats, the changes in GFR and kidney weight correlated with the changes in uEV excretion rate (R = 0.46 and 0.60, P < 0.01). Furthermore, the estimated degree of hypertrophy matched the change in uEV excretion rate (1.4- to 1.5-fold after uninephrectomy and four-fold after 5/6th nephrectomy). Taken together, our data show that uEV excretion depends on nephron mass, and that nephrectomy reduces uEV excretion less than expected based on nephron loss due to compensatory hypertrophy. The major implication of our findings is that a measure for nephron mass or uEV excretion rate should be included when comparing uEV biomarkers between individuals.

Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis.

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have emerged as possible regulators that link epigenetic processes to the metabolism. Here, we discovered a novel role for the NAD+-dependent deacylase SIRT3 in kidney development. In the embryonic kidney, SIRT3 was highly expressed only as a short isoform, with nuclear and extra-nuclear localisation. The nuclear SIRT3 did not act as deacetylase but exerted de-2-hydroxyisobutyrylase activity on lysine residues of histone proteins. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) and Sirt3 deficiency increased PFK Khib levels, inducing a glycolysis boost. This altered Khib landscape in Sirt3-/- metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes.

Generation of Induced Nephron Progenitor-like Cells from Human Urine-Derived Cells.

BACKGROUND: Regenerative medicine strategies employing nephron progenitor cells (NPCs) are a viable approach that is worthy of substantial consideration as a promising cell source for kidney diseases. However, the generation of induced nephron progenitor-like cells (iNPCs) from human somatic cells remains a major challenge. Here, we describe a novel method for generating NPCs from human urine-derived cells (UCs) that can undergo long-term expansion in a serum-free condition. RESULTS: Here, we generated iNPCs from human urine-derived cells by forced expression of the transcription factors OCT4, SOX2, KLF4, c-MYC, and SLUG, followed by exposure to a cocktail of defined small molecules. These iNPCs resembled human embryonic stem cell-derived NPCs in terms of their morphology, biological characteristics, differentiation potential, and global gene expression and underwent a long-term expansion in serum-free conditions. CONCLUSION: This study demonstrates that human iNPCs can be readily generated and expanded, which will facilitate their broad applicability in a rapid, efficient, and patient-specific manner, particularly holding the potential as a transplantable cell source for patients with kidney disease.

Identification of candidate PAX2-regulated genes implicated in human kidney development.

PAX2 is a transcription factor essential for kidney development and the main causative gene for renal coloboma syndrome (RCS). The mechanisms of PAX2 action during kidney development have been evaluated in mice but not in humans. This is a critical gap in knowledge since important differences have been reported in kidney development in the two species. In the present study, we hypothesized that key human PAX2-dependent kidney development genes are differentially expressed in nephron progenitor cells from induced pluripotent stem cells (iPSCs) in patients with RCS relative to healthy individuals. Cap analysis of gene expression revealed 189 candidate promoters and 71 candidate enhancers that were differentially activated by PAX2 in this system in three patients with RCS with PAX2 mutations. By comparing this list with the list of candidate Pax2-regulated mouse kidney development genes obtained from the Functional Annotation of the Mouse/Mammalian (FANTOM) database, we prioritized 17 genes. Furthermore, we ranked three genes-PBX1, POSTN, and ITGA9-as the top candidates based on closely aligned expression kinetics with PAX2 in the iPSC culture system and susceptibility to suppression by a Pax2 inhibitor in cultured mouse embryonic kidney explants. Identification of these genes may provide important information to clarify the pathogenesis of RCS, human kidney development, and kidney regeneration.

[Role of distal nephron in the control of extracellular volume in physiology and in nephrotic syndrome]. / Rôle du néphron distal dans le contrôle du volume extracellulaire en condition physiologique et dans le syndrome néphrotique.

The kidney plays a major role to maintain the constancy of the "milieu intérieur" by adjusting the urinary excretion of water and solutes to the requirement of the body balance. This function is coordinated with elimination of waste products generated among others by the catabolism of proteins and nucleic acids. To cope with these two major functions, the human kidneys generate each day about 180 L of ultrafiltrate from plasma and reabsorbs the vast majority of filtered water and solutes to excrete daily about one-two liter(s) of urine containing concentrations of sodium, potassium and chloride ranging from 20 to 200 mM. The final adjustment of urine composition is finely tuned along the aldosterone-sensitive distal nephron (ASDN) which includes the distal convoluted tubule and the collecting system (connecting tubule and collecting duct). Sodium reabsorption is predominant along the distal tubule if potassium must be spared, or along the collecting system when large amounts of potassium must be secreted. Nephrotic syndrome is characterized by heavy proteinuria consecutive to a glomerular injury, associated with renal sodium and water retention taking initially place along ASDN and leading to edema.

TITLE: Rôle du néphron distal dans le contrôle du volume extracellulaire en condition physiologique et dans le syndrome néphrotique. ABSTRACT: Les reins jouent un rôle majeur dans le maintien de la composition du milieu intérieur. Cette fonction est coordonnée avec l'élimination des déchets du métabolisme, impliquant la production par les reins d'environ 180 litres de filtrat par jour et la réabsorption de la grande majorité de l'eau et des solutés filtrés. L'ajustement final de la composition de l'urine est réalisé dans le segment distal sensible à l'aldostérone (ASDN), qui inclut le tube contourné distal et le système collecteur. La réabsorption de sodium prédomine dans le tube distal si le potassium doit être épargné, ou dans le système collecteur si le potassium doit être sécrété. Le syndrome néphrotique est caractérisé par une protéinurie massive causée par des lésions glomérulaires, associée à une rétention hydrosodée prenant place dans l'ASDN et induisant chez le patient des œdèmes parfois volumineux.

Tubuloglomerular Feedback Synchronization in Nephrovascular Networks.

To perform their functions, the kidneys maintain stable blood perfusion in the face of fluctuations in systemic BP. This is done through autoregulation of blood flow by the generic myogenic response and the kidney-specific tubuloglomerular feedback (TGF) mechanism. The central theme of this paper is that, to achieve autoregulation, nephrons do not work as single units to manage their individual blood flows, but rather communicate electrically over long distances to other nephrons via the vascular tree. Accordingly, we define the nephrovascular unit (NVU) to be a structure consisting of the nephron, glomerulus, afferent arteriole, and efferent arteriole. We discuss features that require and enable distributed autoregulation mediated by TGF across the kidney. These features include the highly variable topology of the renal vasculature which creates variability in circulation and the potential for mismatch between tubular oxygen demand and delivery; the self-sustained oscillations in each NVU arising from the autoregulatory mechanisms; and the presence of extensive gap junctions formed by connexins and their properties that enable long-distance transmission of TGF signals. The existence of TGF synchronization across the renal microvascular network enables an understanding of how NVUs optimize oxygenation-perfusion matching while preventing transmission of high systemic pressure to the glomeruli, which could lead to progressive glomerular and vascular injury.

Effect of fetal growth restriction on urinary podocalyxin levels at birth in preterm neonates.

BACKGROUND: Small-for-gestational-age (SGA) neonates are at a higher risk of adult-onset metabolic disorders because of fetal programming in the presence of growth restriction. Nephrogenesis may also be affected in fetal growth restriction. This study hypothesized that urinary podocalyxin levels, a marker of nephrogenesis, would be lower among preterm SGA neonates as compared to appropriate-for-gestational-age (AGA) controls. METHODS: This cross-sectional study enrolled gestation-matched SGA (n = 90) and AGA (n = 45) neonates born at 260-366 weeks of gestation. The SGA group comprised of 45 neonates with birth weight between 3rd and 10th centile and 45 neonates with birth weight <3rd centile. The primary outcome of the study was the difference in urinary podocalyxin levels between SGA and AGA neonates. Glomerular and tubular functions were also assessed. RESULTS: Urinary podocalyxin levels were similar in SGA and AGA neonates (ng/mg of creatinine; median [interquartile range]: 28.7 [4.8-70.2] vs. 18.7 [3.1-55.9]), P value 0.14). No correlation was observed between birth weight centile and urinary podocalyxin levels (r: -0.06). Glomerular filtration rate, fractional excretion of sodium, and serum ß-2-microglobulin levels were comparable across the study groups. CONCLUSIONS: Glomerular development as assessed by urinary podocalyxin levels and renal functions are comparable in SGA and AGA preterm neonates. IMPACT: Neonates born with fetal growth restriction are at a higher risk of adult-onset metabolic disorders because of fetal programming. This cross-sectional study investigated the effect of presence and severity of fetal growth restriction on glomerular development by measuring urinary podocalyxin levels in preterm infants. This study did not observe any effect of the presence or severity of fetal growth restriction on urinary podocalyxin levels and other markers of glomerular and renal tubular functions.

Facilitated NaCl Uptake in the Highly Developed Bundle of the Nephron in Japanese Red Stingray Hemitrygon akajei Revealed by Comparative Anatomy and Molecular Mapping.

Batoidea (rays and skates) is a monophyletic subgroup of elasmobranchs that diverged from the common ancestor with Selachii (sharks) about 270 Mya. A larger number of batoids can adapt to low-salinity environments, in contrast to sharks, which are mostly stenohaline marine species. Among osmoregulatory organs of elasmobranchs, the kidney is known to be dedicated to urea retention in ureosmotic cartilaginous fishes. However, we know little regarding urea reabsorbing mechanisms in the kidney of batoids. Here, we performed physiological and histological investigations on the nephrons in the red stingray (Hemitrygon akajei) and two shark species. We found that the urine/plasma ratios of salt and urea concentrations in the stingray are significantly lower than those in cloudy catshark (Scyliorhinus torazame) under natural seawater, indicating that the kidney of stingray more strongly reabsorbs these osmolytes. By comparing the three-dimensional images of nephrons between stingray and banded houndshark (Triakis scyllium), we showed that the tubular bundle of stingray has a more compact configuration. In the compact tubular bundle of stingray kidney, the distal diluting tubule was highly developed and frequently coiled around the proximal and collecting tubules. Furthermore, co-expression of NKAα1 (Na+/K +-ATPase) and NKCC2 (Na+- K+-2Cl- cotransporter 2) mRNAs was prominent in the coiled diluting segment. These findings imply that NaCl reabsorption is greatly facilitated in the stingray kidney, resulting in a higher reabsorption rate of urea. Lowering the loss of osmolytes in the glomerular filtrate is likely favorable to the adaptability of batoids to a wide range of environmental salinity.

Sex differences in solute transport along the nephrons: effects of Na+ transport inhibition.

Each day, ~1.7 kg of NaCl and 180 liters of water are reabsorbed by nephron segments in humans, with urinary excretion fine tuned to meet homeostatic requirements. These tasks are coordinated by a spectrum of renal Na+ transporters and channels. The goal of the present study was to investigate the extent to which inhibitors of transepithelial Na+ transport (TNa) along the nephron alter urinary solute excretion and how those effects may vary between male and female subjects. To accomplish that goal, we developed sex-specific multinephron models that represent detailed transcellular and paracellular transport processes along the nephrons of male and female rat kidneys. We simulated inhibition of Na+/H+ exchanger 3 (NHE3), bumetanide-sensitive Na+-K+-2Cl- cotransporter (NKCC2), Na+-Cl- cotransporter (NCC), and amiloride-sensitive epithelial Na+ channel (ENaC). NHE3 inhibition simulations predicted a substantially reduced proximal tubule TNa, and NKCC2 inhibition substantially reduced thick ascending limb TNa. Both gave rise to diuresis, natriuresis, and kaliuresis, with those effects stronger in female rats. While NCC inhibition was predicted to have only minor impact on renal TNa, it nonetheless had a notable effect of enhancing excretion of Na+, K+, and Cl-, particularly in female rats. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+ (increased) and K+ (decreased) and to have only a minor impact on whole kidney TNa. Unlike inhibition of other transporters, ENaC inhibition induced stronger natriuresis and diuresis in male rats than female rats. Overall, model predictions agreed well with measured changes in Na+ and K+ excretion in response to diuretics and Na+ transporter mutations.

Regenerated nephrons in kidney cortices ameliorate exacerbated serum creatinine levels in rats with adriamycin nephropathy.

Kidney regeneration could be classified into 2 groups: kidney generation and kidney repair. We have attempted in vivo nephron generation for kidney repair, as a therapy for chronic renal failure (CRF), by exploiting cellular interactions via conditioned media. In the previous report, we demonstrated the generation of rich nephrons in rat intact kidney cortices through percapsular injection of mesenchymal stem cell (MSC)-differentiated tubular epithelial cells (TECs) after pretreatment of 3-dimensional culture using a small amount of gel complex and condensed medium. In this study, to verify the amelioration of serum creatinine (sCr) levels by regenerated nephrons in rats with CRF, we first created damaged kidneys through systemic administration of adriamycin, and implanted the pretreated MSC-differentiated TECs into unilateral kidney cortices 2 weeks after adriamycin administration (A-2W, that is I-0W). After recovery of acute kidney injury, the control rats without cell implantation showed re-exacerbation of sCr levels, resulting in death within A-12W. Alternatively, the cell-implanted rats had a formation of mature nephrons in I-3W, and showed significant amelioration of sCr levels in I-7W. As a result, these rats could live until euthanization in I-12W or I-16W, indicating the utility of cell injection therapy into a kidney (K-CIT) for CRF. We expect that our K-CIT or the refined methods will be applied to patients with CRF.

Nephron Progenitor Maintenance Is Controlled through Fibroblast Growth Factors and Sprouty1 Interaction.

BACKGROUND: Nephron progenitor cells (NPCs) give rise to all segments of functional nephrons and are of great interest due to their potential as a source for novel treatment strategies for kidney disease. Fibroblast growth factor (FGF) signaling plays pivotal roles in generating and maintaining NPCs during kidney development, but little is known about the molecule(s) regulating FGF signaling during nephron development. Sprouty 1 (SPRY1) is an antagonist of receptor tyrosine kinases. Although SPRY1 antagonizes Ret-GDNF signaling, which modulates renal branching, its role in NPCs is not known. METHODS: Spry1, Fgf9, and Fgf20 compound mutant animals were used to evaluate kidney phenotypes in mice to understand whether SPRY1 modulates FGF signaling in NPCs and whether FGF8 functions with FGF9 and FGF20 in maintaining NPCs. RESULTS: Loss of one copy of Spry1 counters effects of the loss of Fgf9 and Fgf20, rescuing bilateral renal agenesis premature NPC differentiation, NPC proliferation, and cell death defects. In the absence of SPRY1, FGF9, and FGF20, another FGF ligand, FGF8, promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis, defects in NPC proliferation, and cell death. Deleting one copy of Fgf8 reversed the effect of deleting one copy of Spry1, which rescued the renal agenesis due to loss of Fgf9 and Fgf20. CONCLUSIONS: SPRY1 expressed in NPCs modulates the activity of FGF signaling and regulates NPC stemness. These findings indicate the importance of the balance between positive and negative signals during NPC maintenance.

Dietary Protein Intake and Single-Nephron Glomerular Filtration Rate.

High protein intake can increase glomerular filtration rate (GFR) in response to excretory overload, which may exacerbate the progression of kidney disease. However, the direct association between glomerular hemodynamic response at the single-nephron level and dietary protein intake has not been fully elucidated in humans. In the present study, we evaluated nutritional indices associated with single-nephron GFR (SNGFR) calculated based on corrected creatinine clearance (SNGFRCr). We retrospectively identified 43 living kidney donors who underwent enhanced computed tomography and kidney biopsy at the time of donation at Jikei University Hospital in Tokyo from 2007 to 2018. Total nephron number was estimated with imaging-derived cortical volume and morphometry-derived glomerular density. SNGFRCr was calculated by dividing the corrected creatinine clearance by the number of non-sclerosed glomeruli (NglomNSG). The mean (± standard deviation) NglomNSG/kidney and SNGFRCr were 685,000 ± 242,000 and 61.0 ± 23.9 nL/min, respectively. SNGFRCr was directly associated with estimated protein intake/ideal body weight (p = 0.005) but not with body mass index, mean arterial pressure, albumin, or sodium intake. These findings indicate that greater protein intake may increase SNGFR and lead to glomerular hyperfiltration.

Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2-Mediated Blood Pressure Reduction Independent of Cystogenesis.

BACKGROUND: Hypertension often occurs before renal function deteriorates in autosomal dominant polycystic kidney disease (ADPKD). It is unknown whether the Pkd1 gene product polycystin-1-the predominant causal factor in ADPKD-itself contributes to ADPKD hypertension independent of cystogenesis. METHODS: We induced nephron-specific disruption of the Pkd1 gene in 3-month-old mice and examined them at 4-5 months of age. RESULTS: Kidneys from the Pkd1 knockout mice showed no apparent renal cysts, tubule dilation, or increased cell proliferation. Compared with control mice, Pkd1 knockout mice exhibited reduced arterial pressure during high salt intake; this associated with an increased natriuretic, diuretic, and kaliuretic response during the first 2-3 days of salt loading. The lower arterial pressure and enhanced natriuresis during high salt loading in Pkd1 knockout mice were associated with lower urinary nitrite/nitrate excretion and markedly increased urinary PGE2 excretion, whereas GFR, plasma renin concentration, and urinary endothelin-1 excretion were similar between knockout and control mice. Kidney cyclooxygenase-2 protein levels were increased in Pkd1 knockout mice during high salt intake; administration of NS-398, a selective cyclooxygenase-2 inhibitor, abolished the arterial pressure difference between the knockout and control mice during high salt intake. Total kidney Na+/K+/2Cl- cotransporter isoform 2 (NKCC2) levels were greatly reduced in Pkd1 knockout mice fed a high salt diet compared with controls. CONCLUSIONS: These studies suggest that nephron polycystin-1 deficiency does not itself contribute to ADPKD hypertension and that it may, in fact, exert a relative salt-wasting effect. The work seems to comprise the first in vivo studies to describe a potential physiologic role for nephron polycystin-1 in the absence of cysts, tubule dilation, or enhanced cell proliferation.

Formation of Mature Nephrons by Implantation of Human Pluripotent Stem Cell-Derived Progenitors into Mice.

In the future, stem cell-based technologies may be harnessed to replace conventional dialysis and transplantation in patients with diabetic nephropathy. Recently, there has been considerable effort to improve methods for the differentiation of human pluripotent stem cells (hPSCs) into kidney cells in culture. Here, we present a protocol for obtaining more advanced kidney structures than have currently been possible in vitro, including vascularized glomeruli and tubular elements. HPSCs are first differentiated in 2D culture to a kidney progenitor stage. These cells are then dissociated and injected subcutaneously into immunocompromised mice. Twelve weeks later, the cells have developed into mature kidney structures and are excised for further characterization. This method constitutes a significant improvement on protocols that involve either exclusively a 2D culture or placing the cells in 3D organoid culture at the air-liquid interface in vitro.

Mathematical models for kidney function focusing on clinical interest.

We give an overview of mathematical models of renal physiology and anatomy with the clinician in mind. Beyond the past focus on issues of local transport mechanisms along the nephron and the urine concentrating mechanism, recent models have brought insight into difficult problems such as renal ischemia (oxygen and CO2 diffusion in the medulla) or calcium and potassium homeostasis. They have also provided revealing 3D reconstructions of the full trajectories of families of nephrons and collecting ducts through cortex and medulla. The recent appearance of sophisticated whole-kidney models representing nephrons and their associated renal vasculature promises more realistic simulation of renal pathologies and pharmacological treatments in the foreseeable future.