Postnatal prolongation of mammalian nephrogenesis by excess fetal GDNF

ABSTRACT Nephron endowment, defined during the fetal period, dictates renal and related cardiovascular health throughout life. We show here that, despite its negative effects on kidney growth, genetic increase of GDNF prolongs the nephrogenic program beyond its normal cessation. Multi-stage mechanistic analysis revealed that excess GDNF maintains nephron progenitors and nephrogenesis through increased expression of its secreted targets and augmented WNT signaling, leading to a two-part effect on nephron progenitor maintenance. Abnormally high GDNF in embryonic kidneys upregulates its known targets but also Wnt9b and Axin2, with concomitant deceleration of nephron progenitor proliferation. Decline of GDNF levels in postnatal kidneys normalizes the ureteric bud and creates a permissive environment for continuation of the nephrogenic program, as demonstrated by morphologically and molecularly normal postnatal nephron progenitor self-renewal and differentiation. These results establish that excess GDNF has a bi-phasic effect on nephron progenitors in mice, which can faithfully respond to GDNF dosage manipulation during the fetal and postnatal period. Our results suggest that sensing the signaling activity level is an important mechanism through which GDNF and other molecules contribute to nephron progenitor lifespan specification.

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Age-Dependent Changes in the Progenitor Translatome Coordinated in part by Tsc1 Increase Perception of Signaling Inputs to End Nephrogenesis

10.1101/2020.03.12.989343 ◽

2020 ◽

Author(s):

Eric Brunskill ◽

Alison Jarmas ◽

Praneet Chaturvedi ◽

Raphael Kopan

Keyword(s):

Gradual Increase ◽

Tipping Point ◽

Ureteric Bud ◽

Self Renewal ◽

Nephron Endowment ◽

Nephron Progenitors ◽

Age Dependent ◽

Cellular Translation ◽

Nephron Progenitor

AbstractMammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that in young niches, cellular Wnt agonists are poorly translated, Fgf20 levels are high and R-spondin levels are low, resulting in a pro self-renewal environment. By contrast, older niches are low in Fgf20 and high in R-spondin, with increased cellular translation of Wnt agonists, including the signalosome-promoting Tmem59. This suggests a hypothesis that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving differentiation. We show Tsc1 hemizygosity differentially promoted translation of Wnt antagonists over agonists, expanding a transitional (Six2+, Cited1+, Wnt4+) state and delaying the tipping point. As predicted by these findings, reducing Rspo3 dosage in nephron progenitors or Tmem59 globally increased nephron numbers in vivo.

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Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis

Nature Communications ◽

10.1038/s41467-021-26626-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Alison E. Jarmas ◽

Eric W. Brunskill ◽

Praneet Chaturvedi ◽

Nathan Salomonis ◽

Raphael Kopan

Keyword(s):

Progenitor Cells ◽

Gradual Increase ◽

Tipping Point ◽

Ureteric Bud ◽

Self Renewal ◽

Nephron Endowment ◽

Nephron Progenitors ◽

Nephron Progenitor

AbstractMammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that translatome analysis in Tsc1+/− nephron progenitor cells from mice with elevated nephron numbers reveals how differential translation of Wnt antagonists over agonists tips the balance between self-renewal and differentiation. Wnt agonists are poorly translated in young niches, resulting in an environment with low R-spondin and high Fgf20 promoting self-renewal. In older niches we find increased translation of Wnt agonists, including R-spondin and the signalosome-promoting Tmem59, and low Fgf20, promoting differentiation. This suggests that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and possibly clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving synchronized differentiation. As predicted by these findings, removing one Rspo3 allele in nephron progenitors delays cessation and increases nephron numbers in vivo.

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Tumor-free elongation of mammalian nephrogenesis by excess fetal GDNF

10.1101/2020.05.28.120865 ◽

2020 ◽

Author(s):

Hao Li ◽

Jussi Kupari ◽

Yujuan Gui ◽

Edward Siefker ◽

Benson Lu ◽

...

Keyword(s):

Cardiovascular Health ◽

Major Effect ◽

Kidney Tumors ◽

Regenerative Capacity ◽

Self Renewal ◽

Fetal Period ◽

Nephron Endowment ◽

Nephron Progenitors ◽

Neurotropic Factor ◽

Nephron Progenitor

ABSTRACTDue to poor regenerative capacity of adult kidneys, nephron endowment defined by the nephrogenic program during the fetal period dictates renal and related cardiovascular health throughout life. We show that the neurotropic factor GDNF, which is in clinical trials for Parkinson’s disease, is capable of prolonging the nephrogenic program beyond its normal cessation without increasing the risk of kidney tumors. Our data demonstrates that excess GDNF expands the nephrogenic program by maintaining nephron progenitors and nephrogenesis in postnatal mouse kidneys. GDNF, through its transcriptional targets excreted from the adjacent epithelium, has a major effect on nephron progenitor self-renewal and maintenance; abnormally high GDNF inhibits nephron progenitor proliferation, but lowering its level normalizes the nephrogenic program to that permissive for nephron progenitor self-renewal and differentiation. Based on our results, we propose that the lifespan of nephron progenitors is determined by mechanisms related to perception of GDNF and other signaling levels.

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Dicer function is required in the metanephric mesenchyme for early kidney development

AJP Renal Physiology ◽

10.1152/ajprenal.00426.2013 ◽

2014 ◽

Vol 306 (7) ◽

pp. F764-F772 ◽

Cited By ~ 25

Author(s):

Jessica Y. S. Chu ◽

Sunder Sims-Lucas ◽

Daniel S. Bushnell ◽

Andrew J. Bodnar ◽

Jordan A. Kreidberg ◽

...

Keyword(s):

Target Genes ◽

Kidney Development ◽

Metanephric Mesenchyme ◽

Ureteric Bud ◽

Rnase Iii ◽

Nephron Progenitors ◽

Proapoptotic Protein ◽

Kidney Organogenesis ◽

Regulatory Rnas ◽

Nephron Progenitor

MicroRNAs (miRNAs) are small, noncoding regulatory RNAs that act as posttranscriptional repressors by binding to the 3′-untranslated region (3′-UTR) of target genes. They require processing by Dicer, an RNase III enzyme, to become mature regulatory RNAs. Previous work from our laboratory revealed critical roles for miRNAs in nephron progenitors at midgestation (Ho J, Pandey P, Schatton T, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. J Am Soc Nephrol 22: 1053–1063, 2011). To interrogate roles for miRNAs in the early metanephric mesenchyme, which gives rise to nephron progenitors as well as the renal stroma during kidney development, we conditionally ablated Dicer function in this lineage. Despite normal ureteric bud outgrowth and condensation of the metanephric mesenchyme to form nephron progenitors, early loss of miRNAs in the metanephric mesenchyme resulted in severe renal dysgenesis. Nephron progenitors are initially correctly specified in the mutant kidneys, with normal expression of several transcription factors known to be critical in progenitors, including Six2, Pax2, Sall1, and Wt1. However, there is premature loss of the nephron progenitor marker Cited1, marked apoptosis, and increased expression of the proapoptotic protein Bim shortly after the initial inductive events in early kidney development. Subsequently, there is a failure in ureteric bud branching and nephron progenitor differentiation. Taken together, our data demonstrate a previously undetermined requirement for miRNAs during early kidney organogenesis and indicate a crucial role for miRNAs in regulating the survival of this lineage.

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Nephron progenitor maintenance is controlled through FGFs and Sprouty1 Interaction

10.1101/2020.03.26.010421 ◽

2020 ◽

Author(s):

Sung-Ho Huh ◽

Ligyeom Ha ◽

Hee-Seong Jang

Keyword(s):

Cell Death ◽

Tyrosine Kinases ◽

Kidney Development ◽

Renal Agenesis ◽

Treatment Strategies ◽

Loss Of Function ◽

Nephron Progenitors ◽

Novel Treatment Strategies ◽

Nephron Progenitor ◽

Progenitor Maintenance

AbstractThe 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) signal plays pivotal roles in generating and maintaining NPCs during kidney development. However, molecule(s) regulating FGF signal during nephron development is not known. Sprouty (SPRY) is an antagonist of receptor tyrosine kinases. During kidney development, SPRY1 is expressed in the ureteric buds (UBs) and regulates UB branching by antagonizing Ret-GDNF signal. Here, we provide evidence that SPRY1 expressed in NPCs modulates activity of FGF signal in NPCs and regulates NPC stemness. Haploinsufficiency of Spry1 rescues bilateral renal agenesis and premature NPC differentiation caused by loss of Fgf9 and Fgf20. In addition, haploinsufficiency of Spry1 rescues NPC proliferation and cell death defects induced by loss of Fgf9 and Fgf20. In the absence of SPRY1, FGF9 and FGF20, another FGF ligand, FGF8 promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis and defects in NPC proliferation and cell death. Rescue of loss of Fgf9 and Fgf20 induced renal agenesis by Spry1 haploinsufficiency was reversed when one copy of Fgf8 was deleted. These findings indicate the importance of the balance between positive and negative signal during NPC maintenance. Failure of the balance may underlie some human congenital kidney malformation.Significance StatementNephrons are functional units of kidney to filter blood to excrete wastes and regulate osmolarity and ion concentrations. Nephrons are derived from nephron progenitors. Nephron progenitors are depleted during kidney development which makes it unable to regenerate nephrons. Therefore, understanding signaling molecules regulating nephron progenitor generation and maintenance is of great interest for the future kidney regenerative medicine. Here, we show that Sprouty1 regulates nephron progenitor maintenance by inhibiting FGF signal. Deletion of Sprouty1 rescues renal agenesis and nephron progenitor depletion in the Fgf9/20 loss-of-function kidneys. Further decrease of FGF signal by deleting one copy of Fgf8 makes kidneys irresponsive to Sprouty1 resulting in failure of nephron progenitor maintenance. This study thus identifies the reciprocal function of FGF-Sprouty1 signal during nephron progenitor development.

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Testing the Associations Between State and Trait Anxiety, Anger, Sadness, and Ambulatory Blood Pressure and Whether Race Impacts These Relationships

Annals of Behavioral Medicine ◽

10.1093/abm/kaab098 ◽

2021 ◽

Author(s):

Larisa Gavrilova ◽

Matthew J Zawadzki

Keyword(s):

Blood Pressure ◽

Trait Anxiety ◽

Ambulatory Blood Pressure ◽

Cardiovascular Health ◽

Negative Emotions ◽

Anxiety And Depression ◽

Negative Effects ◽

Conditional Effects ◽

Potential Risk Factors ◽

Ecological Momentary

Abstract Background Anxiety, anger, and sadness are related to elevated ambulatory blood pressure (ABP), yet it is unclear whether each emotion exerts unique effects. Moreover, an understanding of who might be most susceptible to the negative effects of these emotions is limited, with the trait tendency to experience them or one’s race as potential moderators. Purpose The study examined the potential for differential effects of momentary anxiety, anger, and sadness on ABP. The study assessed whether a trait tendency to experience these negative emotions and/or race (Black vs. non-Black) would moderate these relationships. Methods Participants (n = 153) completed trait anxiety, anger, and depressive symptoms measures at baseline. ABP was collected over two 24-hour periods 3–4 months apart. Momentary measures of anxiety, anger, and sadness were assessed via ecological momentary assessment (EMA) after each ABP reading. Results Momentary anxiety consistently predicted diastolic blood pressure but not systolic blood pressure. Momentary anger and sadness did not predict blood pressure (BP). Conditional effects were found with momentary anxiety and anger predicting elevated BP in those individuals with trait anxiety/anger at its mean. Trait anxiety and depression consistently predicted heightened BP in Black participants. Trait anger did not moderate the relationships between negative emotions and ABP. Conclusions Findings suggest that momentary anxiety and anger should be given attention as potential risk factors for hypertension and highlight the unique perspective of EMA methods. Black participants who were more anxious and depressed experienced heightened BP, with anxiety and depression providing possible intervention targets in improving racial disparities in cardiovascular health.

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Omics profiling identifies MAPK/ERK pathway as a gatekeeper of nephron progenitor metabolism

10.1101/2021.09.27.461969 ◽

2021 ◽

Author(s):

Hyuk Nam Kwon ◽

Kristen Kurtzeborn ◽

Xing Jin ◽

Bruno Reversade ◽

Sunghyouk Park ◽

...

Keyword(s):

Functional Characterization ◽

Mitogen Activated Protein Kinase ◽

Metabolic Effects ◽

Erk Pathway ◽

Double Knockout ◽

Nephron Progenitor ◽

Progenitor Maintenance

Nephron endowment is defined by fetal kidney growth and it critically dictates renal health in adults. Despite the advances in understanding the molecular regulation of nephron progenitor maintenance, propagation, and differentiation, the causes for low congenital nephron count and contribution of basic metabolism to nephron progenitor regulation remain poorly studied. Here we have analyzed the metabolic effects that depend on and are triggered by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, which is an essential intracellular cascade required for nephron progenitor maintenance. Our combined approach utilizing LC/MS-based metabolomics and transcriptional profiling of MAPK/ERK-deficient cells identified 18 out of total 46 metabolites (38 untargeted and 8 targeted) that were down-regulated. These represent glycolysis, gluconeogenesis, pentose phosphate, glycine, and proline pathways among others. We focused our functional characterization of identified metabolites on pyruvate and proline. Use of in vitro kidney cultures revealed dosage-specific functions for pyruvate in not only controlling ureteric bud branching but also determining progenitor and differentiated (tip-trunk) cell identities. Our in vivo characterization of Pycr1/2 double knockout kidneys revealed functional requirement for proline metabolism in nephron progenitor maintenance. In summary, our results demonstrate that MAPK/ERK cascade regulates energy and amino acid metabolism in developing kidney where these metabolic pathways specifically regulate progenitor preservation.

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Assessing nutritional quality as a ‘vital sign’ of cardiometabolic health

British Journal Of Nutrition ◽

10.1017/s0007114519001016 ◽

2019 ◽

Vol 122 (2) ◽

pp. 195-205

Author(s):

Dorothée Buteau-Poulin ◽

Paul Poirier ◽

Jean-Pierre Després ◽

Natalie Alméras

Keyword(s):

Vital Sign ◽

Nutritional Quality ◽

Cardiovascular Health ◽

Heart Association ◽

Hdl Cholesterol ◽

Activity Level ◽

Cardiometabolic Health ◽

Lifestyle Habits ◽

Ideal Cardiovascular Health ◽

Cholesterol Ratio

AbstractHigh overall nutritional quality (NQ) is an important component of ideal cardiovascular health, a concept introduced in 2010 by the American Heart Association. However, data on the independent contribution of overall NQ to the variation in the cardiometabolic risk (CMR) profile are limited. This observational study aimed to investigate the association between overall NQ and the CMR profile in 4785 participants (65⋅4 % of men, age 43⋅3 (sd 10⋅8) years) who underwent a cardiometabolic health evaluation, including lifestyle habits, anthropometric measurements, blood pressure, lipid profile and HbA1c concentrations. In addition, a submaximal exercise test was conducted to assess cardiorespiratory fitness (CRF). Using a standardised NQ questionnaire (twenty-five items food-based questionnaire), participants were classified into three subgroups: (1) low, (2) moderate or (3) high NQ and variance and multiple linear regression analyses were performed. Results showed that less than 15 % of participants presented a high NQ. A high NQ was associated with a healthier lifestyle habits and a more favourable CMR profile (lower values of waist circumference and cholesterol:HDL-cholesterol ratio, lower concentrations of non-HDL-cholesterol, TAG and HbA1c). Some of these associations were independent of age, physical activity level (PAL) and CRF. A better NQ was also associated with a lower proportion of participants presenting the hypertriacylglycerolaemic waist phenotype independently of both PAL and CRF. The present study suggests that overall NQ can be assessed with a short food-based questionnaire and should be considered in clinical practice as a new ‘vital sign’ associated with other health behaviours and cardiometabolic health.

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Is Drinking Alcohol Really Linked to Cardiovascular Health? Evidence from the Kardiovize 2030 Project

Nutrients ◽

10.3390/nu12092848 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2848

Author(s):

Andrea Maugeri ◽

Ota Hlinomaz ◽

Antonella Agodi ◽

Martina Barchitta ◽

Sarka Kunzova ◽

...

Keyword(s):

Blood Pressure ◽

Alcohol Consumption ◽

Cardiovascular Health ◽

Fasting Glucose ◽

Smoking Status ◽

Activity Level ◽

Drinking Patterns ◽

Drinking Alcohol ◽

Cvd Risk ◽

The Relationship

Existing data have described benefits and drawbacks of alcohol consumption on cardiovascular diseases (CVD), but no research has evaluated its association with the cardiovascular health (CVH) score proposed by the American Heart Association. Here, we conducted a cross-sectional analysis on the Kardiovize cohort (Brno, Czech Republic), to investigate the relationship between alcohol consumption and CVH. We included 1773 subjects (aged 25–64 years; 44.2% men) with no history of CVD. We compared CVD risk factors, CVH metrics (i.e., BMI, healthy diet, physical activity level, smoking status, blood pressure, fasting glucose, and total cholesterol) and CVH score between and within several drinking categories. We found that the relationship between drinking habits and CVH was related to the amount of alcohol consumed, drinking patterns, and beverage choices. Heavy drinkers were more likely to smoke tobacco, and to report diastolic blood pressure, fasting glucose, triglycerides, and low-density lipoprotein (LDL)-cholesterol at higher level than non-drinkers. Among drinkers, however, people who exclusively drank wine exhibited better CVH than those who exclusively drank beer. Although our findings supported the hypothesis that drinking alcohol was related to the CVH in general, further prospective research is needed to understand whether the assessment of CVH should incorporate information on alcohol consumption.

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Early-Life Exposure to the Chinese Famine and Risk of Cognitive Decline

Journal of Clinical Medicine ◽

10.3390/jcm8040484 ◽

2019 ◽

Vol 8 (4) ◽

pp. 484 ◽

Cited By ~ 1

Author(s):

Hongguo Rong ◽

Xiaozhen Lai ◽

Elham Mahmoudi ◽

Hai Fang

Keyword(s):

Cognitive Decline ◽

Cognitive Performance ◽

Early Life ◽

Late Life ◽

Cognitive Status ◽

Word Recall ◽

Long Term Effects ◽

Negative Effects ◽

Multi Stage ◽

Famine Exposure

Previous studies on the Chinese famine suggested long-term effects of early-life famine exposure on health conditions. This study aims to investigate the association between exposure to the Chinese famine of 1959–1961 at different early-life stages and the risk of cognitive decline in adulthood. A total of 6417 adults born between 1952 and 1964 in the 2015 survey data of China Health and Retirement Longitudinal Study were included in this study. Cognitive performance was estimated through a series of comprehensive neuropsychological tests, including the Telephone Interview of Cognitive Status (TICS-10), word recall, and pentagon drawing. Multiple generalized linear model (GLM) was employed to detect the association between multi-stage early-life famine exposure and late-life cognitive performance. Compared with the unexposed group, respondents exposed to famine in the fetal period performed worse in the TICS (difference −0.52, 95% confidence interval (CI): −0.93 to −0.10), word recall (difference −0.46, 95% CI: −0.74 to −0.19), and general cognition (difference −1.05, 95% CI: −1.64 to −0.47). Furthermore, we also found negative effects of famine exposure on performance of word recall and pentagon drawing in the early (word recall difference −0.56, 95% CI: −1.00 to −0.11; pentagon drawing difference −0.76, 95% CI: −1.40 to −0.12), mid (word recall difference −0.46, 95% CI: −0.81 to −0.11; pentagon drawing difference −0.66, 95% CI: −1.16 to −0.16), and late (word recall difference −0.30, 95% CI: −0.55 to −0.04; pentagon drawing difference −0.75, 95% CI: −1.13 to −0.37) childhood-exposed groups. Early-life famine exposure in different stages is positively associated with late-life cognitive decline. Fetal famine exposure might affect the overall cognitive status in adulthood, and childhood famine exposure has potential adverse effects on visuospatial episodic memory.

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