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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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Body weight at commencement of the study (top left panel) and at the end of 20 week diet protocol (top right panel), and 24 hr food intake (bottom left panel) and 24 hr caloric intake (bottom right) in wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = WT-CONT 12, -HFF 13; HET-CONT 11, -HFF 8.
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pone-0073095-g001: Body weight at commencement of the study (top left panel) and at the end of 20 week diet protocol (top right panel), and 24 hr food intake (bottom left panel) and 24 hr caloric intake (bottom right) in wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = WT-CONT 12, -HFF 13; HET-CONT 11, -HFF 8.

Mentions: At 6 weeks of age mice were allocated to control or high fat diets. The bodyweights of HET mice at this age were slightly but significantly lower than WT mice but there were no significant differences between diet groups. After 20 weeks of diet treatment the genotype differences in bodyweight had disappeared and the body weights of HFF WT and HET mice were approximately 14 g greater that CONT WT and HET mice (Pdiet<0.001; Figure 1). There was no significant difference between the groups in food intake, though caloric intake was 25% higher in high fat fed obese mice (Pdiet<0.001; Figure 1).


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)

Body weight at commencement of the study (top left panel) and at the end of 20 week diet protocol (top right panel), and 24 hr food intake (bottom left panel) and 24 hr caloric intake (bottom right) in wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = WT-CONT 12, -HFF 13; HET-CONT 11, -HFF 8.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073095-g001: Body weight at commencement of the study (top left panel) and at the end of 20 week diet protocol (top right panel), and 24 hr food intake (bottom left panel) and 24 hr caloric intake (bottom right) in wildtype (WT; open bars) and GDNF HET (hatched bars) mice fed control (CONT) or high fat (HFF) diet.Data analyzed by two way ANOVA with the factors of genotype (gp), diet and interaction (int; diet x genotype). Values are mean ± SEM. n = WT-CONT 12, -HFF 13; HET-CONT 11, -HFF 8.
Mentions: At 6 weeks of age mice were allocated to control or high fat diets. The bodyweights of HET mice at this age were slightly but significantly lower than WT mice but there were no significant differences between diet groups. After 20 weeks of diet treatment the genotype differences in bodyweight had disappeared and the body weights of HFF WT and HET mice were approximately 14 g greater that CONT WT and HET mice (Pdiet<0.001; Figure 1). There was no significant difference between the groups in food intake, though caloric intake was 25% higher in high fat fed obese mice (Pdiet<0.001; Figure 1).

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