Regulation of nephron progenitor cell lifespan and nephron endowment

Perl, Alison J; Schuh, Meredith P.; Kopan, Raphael

doi:10.1038/s41581-022-00620-w

Cited by 16 publications

(11 citation statements)

References 191 publications

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“…7 Lower nephron endowment in dogs than in humans also may obligate the use of a more sensitive kidney biomarker or biomarker transformation capable of earlier detection of stable or progressive CKD. In humans, the number of nephrons can vary 10-fold (200 000 to 2 million) per kidney [24][25][26] and has been shown to be of particular relevance as a factor in the development of CKD. 25 In dogs, nephron endowment is lower, especially for certain breeds (eg, 445 000-589 000 nephrons per kidney in beagles).…”

Section: Slope Analysismentioning

confidence: 99%

Differentiation of stable kidney function versus progressive dysfunction in dogs

Cowgill,

Segev,

Vaden

et al. 2023

Veterinary Internal Medicne

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BackgroundCirculating creatinine and symmetric dimethylarginine (SDMA) are biomarkers of kidney function that have been used variously to define stable vs progressive chronic kidney disease (CKD). Slope monitoring of inverse biomarker values (creatinine−1 or SDMA−1) has shown promise, but quantitative criteria to distinguish stable vs progressive CKD using this approach are lacking.ObjectiveAssessment of creatinine−1 and SDMA−1 slope cutoffs to distinguish stable vs progressive CKD.AnimalsOne hundred ten clinically healthy university staff‐owned dogs and 29 male colony dogs with progressive X‐linked hereditary nephropathy (XLHN).MethodsRetrospective analysis combining 2 prospective observational studies, 1 tracking kidney function biomarkers in healthy dogs (HDs) to a maximum of 3 years, and 1 tracking kidney function biomarkers in male colony dogs with progressive XLHN to a maximum of 1 year. The minimum slope of creatinine−1 or SDMA−1 as measured using the IDEXX SDMA test from HD was assigned as the slope cutoff for stable kidney function.ResultsThe stable vs progressive slope cutoff was −0.0119 week × dL/mg for creatinine−1 and −0.0007 week × dL/μg for SDMA−1.Conclusions and Clinical ImportanceIn the studied CKD population, progressive dysfunction can be distinguished from stable kidney function by using the slope of creatinine−1 or SDMA−1. These criteria may serve to characterize CKD in other cohorts of dogs and to establish guidelines for degrees of progression rate in dogs with naturally occurring CKD.

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Section: Slope Analysismentioning

confidence: 99%

Differentiation of stable kidney function versus progressive dysfunction in dogs

Cowgill,

Segev,

Vaden

et al. 2023

Veterinary Internal Medicne

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“…While many genetic and environmental factors can impact nephron number 10 , the list is currently incomplete. While this modified transgene will provide an improved reagent for investigating NPCs without significant disruption to normal nephron formation, a minimally disruptive redesign of the transgene will be required to ensure viability.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the mammalian nephron number (endowment) can only decline with age and is a critical determinant of disease-free survival. In humans, nephron endowment varies by 10-fold 9 , and low nephron number is associated with increased risk of hypertension and chronic kidney disease 10 . Identifying the genetic and molecular mechanisms regulating nephron number establishment could inform therapeutic approaches to support kidney function across the lifespan of vulnerable populations, such as those born prematurely 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Mouse models provide a tractable experimental system for evaluating the effects of genetic background, allelic manipulations, or the environment on nephron number 10 . We complemented published chromatin accessibility (ATAC-seq) datasets 11 with chromatin conformation capture (Hi-C) in NPCs isolated from mouse strains and mutants with variable nephron numbers, and matching ATAC-seq datasets from NPCs at different developmental timepoints to seek shared factors that might promote high nephron number.…”

Section: Introductionmentioning

confidence: 99%

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Reduced nephron endowment in the commonSix2-TGC^tgmouse line is due toSix3misexpression by aberrant enhancer-promoter interactions in the transgene

Perl,

Liu,

Hass

et al. 2023

Preprint

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Lifelong kidney function relies on the complement of nephrons generated during mammalian development from a mesenchymal nephron progenitor cell (NPC) population. Low nephron endowment confers increased susceptibility to chronic kidney disease. We asked whether reduced nephron numbers in the popularSix2TGCtransgenic mouse line1was due to disruption of a regulatory gene at the integration site or to ectopic expression of a gene(s) contained within the transgene. Targeted locus amplification identified integration of theSix2TGCtransgene within an intron ofCntnap5aon chr1. We generated Hi-C datasets from NPCs isolated from theSix2TGCtg/+mice, theCited1CreERT2/+control mice, and theSix2TGCtg/+;Tsc1+/Flox,2mice that exhibited restored nephron number compared withSix2TGCtg/+mice, and mapped the precise integration ofSix2TGCandCited1CreERT2transgenes to chr1 and chr14, respectively. No changes in topology, accessibility, or expression were observed within the 50-megabase region centered onCntnap5ainSix2TGCtg/+mice compared with control mice. By contrast, we identified an aberrant regulatory interaction between aSix2distal enhancer and theSix3promoter contained within the transgene. Increasing theSix2TGCtgtoSix2locus ratio or removing oneSix2allele inSix2TGCtg/+mice, caused severe renal hypoplasia. Furthermore, CRISPR disruption ofSix3within the transgene (Six2TGCΔSix3CT) restored nephron endowment to wildtype levels and abolished the stoichiometric effect. Data from genetic and biochemical studies together suggest that inSix2TGC,SIX3 interferes with SIX2 function in NPC renewal through its C-terminal domain.SignificanceUsing high-resolution chromatin conformation and accessibility datasets we mapped the integration site of two popular transgenes used in studies of nephron progenitor cells and kidney development. Aberrant enhancer-promoter interactions drive ectopic expression ofSix3in theSix2TGCtgline which was correlated with disruption of nephrogenesis. Disruption ofSix3within the transgene restored nephron numbers to control levels; further genetic and biochemical studies suggest thatSix3interferes withSix2-mediated regulation of NPC renewal.

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“…The kidney is the main organ responsible for blood filtration and excretion of xenophobic substances [ 1 ], the nephron being its functional unit [ 2 , 3 ]. The nephron endowment is limited, and the number of nephrons varies widely between individuals in a tenfold magnitude [ 4 , 5 ]. Kidney pathologies include acute kidney injury [ 6 ], between 7 and 90 days, this injury is termed acute kidney disease [ 7 ]; and chronic kidney disease can be defined by a decreased kidney function of at least 3 months duration shown by glomerular filtration rate deficit, and/or markers of kidney damage, despite the underlying cause [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Bismuth Exposure on the Human Kidney—A Systematic Review

et al. 2022

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The effects of bismuth toxicity on the kidney—the main organ responsible for blood filtration—were systematically reviewed. This review was motivated by availability of several sources of bismuth in contact with humans including environmental, medications, dental materials, and cosmetics, potentially leading to kidney filtration of this chemical. No previous studies have systematically reviewed the literature considering this association. A total of 22 studies with a total of 46 individuals met the inclusion criteria, 19 being case reports with only one patient enrolled. The included studies publication dates ranged from 1961 to 2021 and the countries of publication were the United States of America, United Kingdom, Germany, Turkey, Switzerland, and Canada. Bismuth sources affecting the kidneys were uniquely reported as from medical purposes and mostly associated to overdoses with several symptoms, apparently with dose-dependent consequences. Patient history of renal impairment seemed to affect the outcome of the case. Several therapies were conducted following bismuth intoxication, and few studies performed renal biopsies describing its histological findings. It is crucial to reconsider the nephrotoxicity of bismuth compounds, mainly in patients with previous history of renal impairment.

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Regulation of nephron progenitor cell lifespan and nephron endowment

Cited by 16 publications

References 191 publications

Differentiation of stable kidney function versus progressive dysfunction in dogs

Differentiation of stable kidney function versus progressive dysfunction in dogs

Reduced nephron endowment in the commonSix2-TGC^tgmouse line is due toSix3misexpression by aberrant enhancer-promoter interactions in the transgene

Effects of Bismuth Exposure on the Human Kidney—A Systematic Review

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Regulation of nephron progenitor cell lifespan and nephron endowment

Cited by 16 publications

References 191 publications

Differentiation of stable kidney function versus progressive dysfunction in dogs

Differentiation of stable kidney function versus progressive dysfunction in dogs

Reduced nephron endowment in the commonSix2-TGCtgmouse line is due toSix3misexpression by aberrant enhancer-promoter interactions in the transgene

Effects of Bismuth Exposure on the Human Kidney—A Systematic Review

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Reduced nephron endowment in the commonSix2-TGC^tgmouse line is due toSix3misexpression by aberrant enhancer-promoter interactions in the transgene