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Does a nephron deficit exacerbate the renal and cardiovascular effects of obesity?

Gurusinghe S, Brown RD, Cai X, Samuel CS, Ricardo SD, Thomas MC, Kett MM - PLoS ONE (2013)

Bottom Line: It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity.Obesity induced glomerulomegaly, glomerulosclerosis, tubulointerstitial expansion and increased collagen accumulation (total, collagen I, V and IV; Pdiet<0.001).Whilst modest, our findings support the hypothesis that a reduced nephron endowment increases the susceptibility to obesity-induced kidney disease and hypertension.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Monash University, Clayton, Victoria, Australia.

ABSTRACT
It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity. We therefore examined the impact of diet-induced obesity on renal structure and function, and arterial pressure in a genetic model of reduced nephron endowment, the GDNF Heterozygous (HET) mouse. 6 wk-old male GDNF WT and HET mice were placed on control or high fat (HFF) diet for 20 weeks. 24 hr arterial pressure, heart rate and activity (radiotelemetry), creatinine clearance and albumin excretion were measured, and kidneys collected (histopathology, collagen content). Bodyweights of HFF WT (50.6 ± 1.2 g) and HET (48.8 ± 1.4 g) mice were ∼14 g greater than control mice (37.3 ± 1.3 g, 36.4 ± 1.1 g respectively; Pdiet<0.001). Obesity led to significantly greater 24 hr MAP (Pdiet<0.001), heart rate (Pdiet<0.01) and lower locomotor activity (Pdiet<0.01) in HET and WT mice. Whilst there was no significant impact of genotype on 24 hr MAP response to obesity, night-time MAP of obese HET mice was significantly greater than obese WT mice (122.3 ± 1.6 vs 116.9 ± 1.3 mmHg; P<0.05). 24 hr creatinine clearance was 50%, and albumin excretion 180% greater in obese WT and HET mice compared to controls (Pdiet<0.05) but this response did not differ between genotypes. Obesity induced glomerulomegaly, glomerulosclerosis, tubulointerstitial expansion and increased collagen accumulation (total, collagen I, V and IV; Pdiet<0.001). Obese GDNF HET mice had exacerbated total renal collagen (P<0.01), and greater levels of the collagen I subtype compared to kidneys of obese WT mice. In summary, obese nephron-deficient GDNF HET mice were able to maintain the high creatinine clearances of obese WT mice but at the expense of higher MAP and greater renal fibrosis. Whilst modest, our findings support the hypothesis that a reduced nephron endowment increases the susceptibility to obesity-induced kidney disease and hypertension.

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24hour urine production, creatinine clearance and 24 hr albumin excretion of wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Parameters are expressed in absolute (top panels) values and values adjusted for bodyweight (lower panels). Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = 7–13 per group.
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pone-0073095-g003: 24hour urine production, creatinine clearance and 24 hr albumin excretion of wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Parameters are expressed in absolute (top panels) values and values adjusted for bodyweight (lower panels). Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = 7–13 per group.

Mentions: Measures of 24 hr conscious renal function are presented in Figure 3 as both absolute values and values and corrected for bodyweight. Urine production in HET mice was significantly greater than WT mice (Pgp<0.05) in absolute terms and when adjusted for bodyweight (Pgp<0.05). Obesity did not impact on absolute urine production but resulted in a lower urine production per g bodyweight. There was no significant difference in the urine production response of the genotypes to diet-induced obesity. All differences in urine production were reflected in similar differences in water consumption (data not shown). There were no significant differences in creatinine clearance between WT and HET mice measured as either absolute or adjusted for bodyweight. Obese WT and HET mice had creatinine clearances that were over 50% greater than control mice (Pdiet<0.05; Figure 3), an affect that was similar between the two strains. When adjusted for body weights however there were no longer any significant differences in creatinine clearances across the 4 groups. 24hour albumin excretion was not significantly different between the genotypes but was 3-fold higher in obese WT and HET mice compared to control WT and HET mice (Pdiet<0.001; Figure 3). The higher albumin excretion in obese WT and HET mice persisted when values were adjusted for bodyweight (Pdiet<0.001). There was no significant difference in the albuminuria response of WT and HET mice to obesity. Albumin to creatinine ratio showed a similar pattern to albumin excretion (Data not shown).


Does a nephron deficit exacerbate the renal and cardiovascular effects of obesity?

Gurusinghe S, Brown RD, Cai X, Samuel CS, Ricardo SD, Thomas MC, Kett MM - PLoS ONE (2013)

24hour urine production, creatinine clearance and 24 hr albumin excretion of wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Parameters are expressed in absolute (top panels) values and values adjusted for bodyweight (lower panels). Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = 7–13 per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760915&req=5

pone-0073095-g003: 24hour urine production, creatinine clearance and 24 hr albumin excretion of wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Parameters are expressed in absolute (top panels) values and values adjusted for bodyweight (lower panels). Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = 7–13 per group.
Mentions: Measures of 24 hr conscious renal function are presented in Figure 3 as both absolute values and values and corrected for bodyweight. Urine production in HET mice was significantly greater than WT mice (Pgp<0.05) in absolute terms and when adjusted for bodyweight (Pgp<0.05). Obesity did not impact on absolute urine production but resulted in a lower urine production per g bodyweight. There was no significant difference in the urine production response of the genotypes to diet-induced obesity. All differences in urine production were reflected in similar differences in water consumption (data not shown). There were no significant differences in creatinine clearance between WT and HET mice measured as either absolute or adjusted for bodyweight. Obese WT and HET mice had creatinine clearances that were over 50% greater than control mice (Pdiet<0.05; Figure 3), an affect that was similar between the two strains. When adjusted for body weights however there were no longer any significant differences in creatinine clearances across the 4 groups. 24hour albumin excretion was not significantly different between the genotypes but was 3-fold higher in obese WT and HET mice compared to control WT and HET mice (Pdiet<0.001; Figure 3). The higher albumin excretion in obese WT and HET mice persisted when values were adjusted for bodyweight (Pdiet<0.001). There was no significant difference in the albuminuria response of WT and HET mice to obesity. Albumin to creatinine ratio showed a similar pattern to albumin excretion (Data not shown).

Bottom Line: It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity.Obesity induced glomerulomegaly, glomerulosclerosis, tubulointerstitial expansion and increased collagen accumulation (total, collagen I, V and IV; Pdiet<0.001).Whilst modest, our findings support the hypothesis that a reduced nephron endowment increases the susceptibility to obesity-induced kidney disease and hypertension.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Monash University, Clayton, Victoria, Australia.

ABSTRACT
It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity. We therefore examined the impact of diet-induced obesity on renal structure and function, and arterial pressure in a genetic model of reduced nephron endowment, the GDNF Heterozygous (HET) mouse. 6 wk-old male GDNF WT and HET mice were placed on control or high fat (HFF) diet for 20 weeks. 24 hr arterial pressure, heart rate and activity (radiotelemetry), creatinine clearance and albumin excretion were measured, and kidneys collected (histopathology, collagen content). Bodyweights of HFF WT (50.6 ± 1.2 g) and HET (48.8 ± 1.4 g) mice were ∼14 g greater than control mice (37.3 ± 1.3 g, 36.4 ± 1.1 g respectively; Pdiet<0.001). Obesity led to significantly greater 24 hr MAP (Pdiet<0.001), heart rate (Pdiet<0.01) and lower locomotor activity (Pdiet<0.01) in HET and WT mice. Whilst there was no significant impact of genotype on 24 hr MAP response to obesity, night-time MAP of obese HET mice was significantly greater than obese WT mice (122.3 ± 1.6 vs 116.9 ± 1.3 mmHg; P<0.05). 24 hr creatinine clearance was 50%, and albumin excretion 180% greater in obese WT and HET mice compared to controls (Pdiet<0.05) but this response did not differ between genotypes. Obesity induced glomerulomegaly, glomerulosclerosis, tubulointerstitial expansion and increased collagen accumulation (total, collagen I, V and IV; Pdiet<0.001). Obese GDNF HET mice had exacerbated total renal collagen (P<0.01), and greater levels of the collagen I subtype compared to kidneys of obese WT mice. In summary, obese nephron-deficient GDNF HET mice were able to maintain the high creatinine clearances of obese WT mice but at the expense of higher MAP and greater renal fibrosis. Whilst modest, our findings support the hypothesis that a reduced nephron endowment increases the susceptibility to obesity-induced kidney disease and hypertension.

Show MeSH
Related in: MedlinePlus