Estimating Nephron Number in the Developing Kidney Using the Physical Disector/Fractionator Combination

Low glomerular (nephron) endowment has been associated with an increased risk of cardiovascular and renal disease in adulthood. Nephron endowment in humans is determined by 36 wk of gestation, while in rats and mice nephrogenesis ends several days after birth. Specific genes and environmental perturbations have been shown to regulate nephron endowment. Until now, design-based method for estimating nephron number in developing kidneys was unavailable. This was due in part to the difficulty associated with unambiguously identifying developing glomeruli in histological sections. Here, we describe a method that uses lectin histochemistry to identify developing glomeruli and the physical disector/fractionator principle to provide unbiased estimates of total glomerular number ( Nglom). We have characterized Nglom throughout development in kidneys from 76 rats and model this development with a 5-parameter logistic equation to predict Nglom from embryonic day 17.25 to adulthood ( r2 = 0.98). This approach represents the first design-based method with which to estimate Nglom in the developing kidney.

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Estimating Total Nephron Number in the Adult Kidney Using the Physical Disector/Fractionator Combination

Kidney Development - Methods in Molecular Biology ◽

10.1007/978-1-61779-851-1_30 ◽

2012 ◽

pp. 333-350 ◽

Cited By ~ 33

Author(s):

Luise A. Cullen-McEwen ◽

Rebecca N. Douglas-Denton ◽

John F. Bertram

Keyword(s):

Nephron Number ◽

Adult Kidney ◽

Physical Disector

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NEPHRON NUMBER IN THE OFFSPRING OF RATS FED A LOW PROTEIN DIET DURING PREGNANCY

Image Analysis & Stereology ◽

10.5566/ias.v19.p219-222 ◽

2011 ◽

Vol 19 (3) ◽

pp. 219 ◽

Cited By ~ 16

Author(s):

Monika A Zimanyi ◽

John F Bertram ◽

Jane M Black

Keyword(s):

Intrauterine Growth Retardation ◽

Experimental Studies ◽

Protein Diet ◽

Low Protein Diet ◽

Nephron Number ◽

Intrauterine Growth ◽

Nephron Endowment ◽

Low Protein ◽

Normal Protein Diet ◽

Physical Disector

In experimental studies it has been shown that intrauterine growth retardation and reduced kidney growth during development are associated with significant decreases in nephron endowment. However, the results of previous studies may be inaccurate as nephron counts were obtained using a maceration technique, which can lead to breakdown of glomeruli, and other potentially biased techniques. In the present study, the total number of glomeruli (and thereby nephrons) in the offspring of rats fed a low (9%) or normal (20%) protein diet during pregnancy were estimated using a physical disector/fractionator technique. The offspring of rats fed a low protein diet had a significantly lower birth weight than rats fed a normal protein diet, their kidneys were smaller and they contained 30% fewer nephrons (20,386 ± 4,818 in the low protein diet vs. 28,731 ± 3,290 in the control rats). Our results, obtained using an unbiased stereological technique confirm previous findings that administration of a low protein diet during pregnancy results in reduced nephron endowment in the offspring.

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GLOMERULAR NUMBER AND CAPILLARY DIMENSIONS IN THE NORMAL LAMB KIDNEY

Image Analysis & Stereology ◽

10.5566/ias.v21.p157-164 ◽

2011 ◽

Vol 21 (3) ◽

pp. 157 ◽

Cited By ~ 2

Author(s):

Julian Brown ◽

Todd A Briscoe ◽

Richard Harding ◽

Megan L Cock ◽

John F Bertram ◽

...

Keyword(s):

Surface Area ◽

Later Life ◽

Renal Pathology ◽

Renal Development ◽

Nephron Number ◽

Capillary Surface ◽

Capillary Length ◽

Nephron Endowment ◽

Physical Disector ◽

Filtration Surface

Reduced nephron endowment, either inherited or acquired, has been linked to adult renal pathology as well as hypertension. The sheep provides an excellent model for studying nephrogenesis and renal development because, as in humans, nephrogenesis is complete before birth. In the present study, the physical disector/fractionator method was used to estimate the total number of glomeruli, and thereby nephrons, in normal lambs. Glomerular capillary parameters including mean capillary length per glomerulus, mean capillary surface area per glomerulus and total renal filtration surface area (TRFSA) were also estimated. Total glomerular, and hence nephron number was 333,832 ± 69,560 (mean± standard deviation). TRFSA was 10.95 ± 3.64 x 104 mm2• These results establish a methodology for future investigations, using the sheep as a model, into the effects of depleted nephrogenesis on renal pathology in later life.

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Faculty Opinions recommendation of The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1398962.873061 ◽

2010 ◽

Author(s):

David Salant ◽

Ramon Bonegio

Keyword(s):

Developing Kidney ◽

Nephron Segmentation

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Faculty Opinions recommendation of Pax 2/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.21356.478844 ◽

2006 ◽

Author(s):

Jing Yu

Keyword(s):

Developing Kidney

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Faculty Opinions recommendation of Reduced nephron number and glomerulomegaly in Australian Aborigines: a group at high risk for renal disease and hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.30445.486944 ◽

2006 ◽

Author(s):

Peter Tipping

Keyword(s):

High Risk ◽

Renal Disease ◽

Nephron Number ◽

Australian Aborigines

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Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins

International Journal of Molecular Sciences ◽

10.3390/ijms22052298 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2298

Author(s):

Chien-Ning Hsu ◽

You-Lin Tain

Keyword(s):

Kidney Disease ◽

Current Knowledge ◽

Current Evidence ◽

Developmental Origins ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Health And Disease ◽

Nitric Oxide Deficiency ◽

Developing Kidney ◽

Prevention Of Hypertension

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.

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