When the progresses in neonatology lead to severe congenital nephron deficit: is there a pilot in the NICU?

The Munich Wistar Frömter (MWF) rat represents a genetic model with an inherited nephron deficit and exhibits mild hypertension and progressive albuminuria, which is more pronounced in males than females. Previously, we demonstrated in a consomic strain that replacement of a quantitative trait locus on chromosome 6 normalized the nephron deficit and suppressed albuminuria development, suggesting a link between the two findings. Here we tested the role of a second major locus linked to albuminuria in MWF on chromosome 8 and generated the consomic strain MWF-8SHR by transfer of chromosome 8 from spontaneously hypertensive rats (SHR) into MWF. The early onset of albuminuria at 8 wk of age in MWF (>50-fold increase compared with SHR) was significantly suppressed in consomic animals, and the development of marked proteinuria at 32 wk significantly diminished. Total nephron number in consomic rats (23,771 ± 1,352) and MWF (27,028 ± 1,322) were similar and significantly lower (−36%) compared with SHR (36,979 ± 1,352, P < 0.0001). The development of mild albuminuria in female MWF was also significantly diminished in MWF-8SHR. Thus, the development of overt and mild albuminuria in male and female MWF rats is not a mandatory consequence of the inherited nephron deficit. The locus on chromosome 8 appears of interest, because its exchange between MWF and SHR protects against the development of albuminuria in MWF-8SHR animals despite their inherited nephron deficit and higher systolic blood pressure.

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Glomerular surface area is normalized in mice born with a nephron deficit: no role for AT1 receptors

AJP Renal Physiology ◽

10.1152/ajprenal.90359.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. F583-F589 ◽

Cited By ~ 9

Author(s):

Amany Shweta ◽

Luise A. Cullen-McEwen ◽

Michelle M. Kett ◽

Roger G. Evans ◽

Kate M. Denton ◽

...

Keyword(s):

Surface Area ◽

Time Course ◽

Receptor Activation ◽

Compensatory Hypertrophy ◽

Glomerular Hypertrophy ◽

Capillary Surface ◽

Glomerular Capillary ◽

Additional Group ◽

Nephron Deficit ◽

Glomerular Capillaries

We examined whether deficits in glomerular capillary surface area associated with a congenital nephron deficit could be corrected by glomerular hypertrophy. Using unbiased stereological techniques, we examined the time course and mode of glomerular hypertrophy in mice lacking one allele for glial cell line-derived neurotrophic factor (GDNF). These GDNF heterozygous (Het) mice are born with ∼30% less nephrons than wild-type (WT) littermates. An additional group of GDNF Het mice received the angiotensin type 1 (AT1)-receptor antagonist candesartan (Cand; 10 mg·kg−1·day−1) from 5 wk of age to determine the role of AT1 receptors in the compensatory hypertrophy. At 10 wk of age, the total volume of renal corpuscles, glomerular capillary surface area, and length of glomerular capillaries in the kidneys of GDNF Het mice were all markedly (∼45%) less than that of WT mice ( P < 0.001). However, by 30 wk, and persisting at 60 wk of age, GDNF Het and WT mice did not significantly differ in any of these parameters. Furthermore, conscious 24-h mean arterial pressure (MAP) did not differ between GDNF Het and WT mice at any time point. MAP of GDNF Het-Cand mice was 20–30 mmHg less than that of GDNF Het-vehicle mice at all three ages, but Cand treatment did not significantly alter glomerular capillary dimensions. In conclusion, we have demonstrated that the deficit in glomerular capillary surface area associated with a congenital nephron deficit can be corrected for in adulthood by an increase in the total length of glomerular capillaries. This process does not require AT1 receptor activation.

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Early defect in branching morphogenesis of the ureteric bud in induced nephron deficit

Kidney International ◽

10.1038/ki.1996.377 ◽

1996 ◽

Vol 50 (3) ◽

pp. 783-795 ◽

Cited By ~ 28

Author(s):

Thierry Gilbert ◽

Christian Cibert ◽

Evelyne Moreau ◽

Gérard Géraud ◽

Claudie Merlet-Bénichou

Keyword(s):

Branching Morphogenesis ◽

Ureteric Bud ◽

Nephron Deficit

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Combining new tools to assess renal function and morphology: a holistic approach to study the effects of aging and a congenital nephron deficit

AJP Renal Physiology ◽

10.1152/ajprenal.00329.2015 ◽

2017 ◽

Vol 313 (3) ◽

pp. F576-F584 ◽

Cited By ~ 6

Author(s):

Stefania Geraci ◽

Jorge Chacon-Caldera ◽

Luise Cullen-McEwen ◽

Lothar R. Schad ◽

Carsten Sticht ◽

...

Keyword(s):

Renal Function ◽

Ex Vivo ◽

Fluorescein Isothiocyanate ◽

Volume Distribution ◽

Glomerular Hypertrophy ◽

Functional Changes ◽

Glomerular Number ◽

Age Related ◽

Nephron Loss ◽

Nephron Deficit

Recently, new methods for assessing renal function in conscious mice (transcutaneous assessment) and for counting and sizing all glomeruli in whole kidneys (MRI) have been described. In the present study, these methods were used to assess renal structure and function in aging mice, and in mice born with a congenital low-nephron endowment. Age-related nephron loss was analyzed in adult C57BL/6 mice (10–50 wk of age), and congenital nephron deficit was assessed in glial cell line-derived neurotrophic factor heterozygous (GDNF HET)-null mutant mice. Renal function was measured through the transcutaneous quantitation of fluorescein isothiocyanate-sinistrin half-life ( t1/2) in conscious mice. MRI was used to image, count, and size cationic-ferritin labeled glomeruli in whole kidneys ex vivo. Design-based stereology was used to validate the MRI measurements of glomerular number and mean volume. In adult C57BL/6 mice, older age was associated with fewer and larger glomeruli, and a rightward shift in the glomerular size distribution. These changes coincided with a decrease in renal function. GNDF HET mice had a congenital nephron deficit that was associated with glomerular hypertrophy and exacerbated by aging. These findings suggest that glomerular hypertrophy and hyperfiltration are compensatory processes that can occur in conjunction with both age-related nephron loss and congenital nephron deficiency. The combination of measurement of renal function in conscious animals and quantitation of glomerular number, volume, and volume distribution provides a powerful new tool for investigating aspects of renal aging and functional changes.

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Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00481.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R453-R461 ◽

Cited By ~ 72

Author(s):

Hayley Dickinson ◽

David W. Walker ◽

E. Marelyn Wintour ◽

Karen Moritz

Keyword(s):

Blood Pressure ◽

Branching Morphogenesis ◽

Spiny Mouse ◽

Pcr Analysis ◽

Nephron Number ◽

Unbiased Stereology ◽

Expression Of Genes ◽

Basal Blood Pressure ◽

First Time ◽

Nephron Deficit

We investigated the effects of maternal glucocorticoid exposure in the spiny mouse, a precocial species with a relatively long gestation, few offspring, and in which nephrogenesis is complete before birth. We hypothesized that exposure of the fetus to glucocorticoids before the formation of glomeruli would result in adult hypertensive offspring with fewer nephrons. Furthermore, we hypothesized that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at midgestation ( day 20) delivered dexamethasone (dex; 125 μg/kg) or saline for 60 h. Females were killed at day 23 of gestation and kidneys were frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 wk of age, blood pressure was measured in the offspring for 1 wk before nephron number was determined using unbiased stereology. Males and females exposed to dex had significantly fewer nephrons (male: saline: 7,870 ± 27, dex: 6,878 ± 173; female: saline: 7,526 ± 62, dex: 5,886 ± 382; P < 0.001) compared with controls. Dex had no effect on basal blood pressure. Fetal kidneys collected at day 23 of gestation from dex-exposed mothers showed increased mRNA expression of BMP4 ( P < 0.05), TGF-β1 ( P < 0.05), genes known to inhibit branching morphogenesis and gremlin ( P < 0.01), an antagonist of BMP4, compared with saline controls. This study shows for the first time an upregulation of branching morphogenic genes in the fetal kidney in a model of excess maternal glucocorticoids that leads to a nephron deficit in the adult. This study also provides evidence that a reduced nephron number does not necessarily lead to development of hypertension.

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Development of progressive albuminuria in male Munich Wistar Frömter rats is androgen dependent

Physiological Genomics ◽

10.1152/physiolgenomics.00008.2015 ◽

2015 ◽

Vol 47 (7) ◽

pp. 281-289

Author(s):

Laura Herlan ◽

Johannes Unland ◽

Sebastian Langer ◽

Leonard Schulte ◽

Sabrina Schütten ◽

...

Keyword(s):

Androgen Receptor ◽

Urinary Albumin Excretion ◽

Urinary Albumin ◽

Male Rats ◽

Significant Suppression ◽

Tubular Injury ◽

Main Study ◽

Androgen Receptor Antagonist ◽

Renal Tubular ◽

Nephron Deficit

Munich Wistar Frömter (MWF) rats develop spontaneous albuminuria that is linked to autosomal genetic loci and inherit a nephron deficit in both female and male animals, respectively. However, albuminuria and kidney damage are clearly more pronounced in males. Here we tested whether androgens and the androgen receptor influence albuminuria in male MWF. We first demonstrated in a pilot study that orchiectomy (Ox) of male MWF led to a significant suppression of urinary albumin excretion (UAE), while continuous testosterone supplementation in MWF Ox led to UAE levels similar to sham-operated (Sham) MWF rats. Subsequently, we performed a comparative main study between male MWF and normal Wistar rats to evaluate the effect of the androgen receptor on UAE development in adult animals up to the age of 18 wk. MWF Sham developed a marked increase in UAE compared with Wistar Sham (48.30 ± 6.16 vs. 0.42 ± 0.08 mg/24 h, P < 0.0001). UAE was significantly lower in MWF Ox compared with MWF Sham (−55%, P < 0.0001). In MWF Ox animals supplemented with testosterone and treated with the androgen receptor antagonist flutamide (OxTF) UAE at 18 wk was even lower compared with MWF Ox (−71%, P < 0.01) and similar to age-matched female MWF. The mRNA expression of renal tubular injury markers Kim1 and NGAL was increased in MWF Sham compared with Wistar Sham ( P < 0.0008, respectively) and expression decreased significantly in MWF OxTF ( P < 0.0004, respectively). Thus, the sexual dimorphism in albuminuria development in MWF can be attributed to testosterone and the androgen receptor in male rats.

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