Limits...
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.

Show MeSH

Related in: MedlinePlus

Typical histological features of kidneys of wildtype (WT) and GDNF HET mice fed control (CONT) or high fat (HFF) diet.Panels A-F: High power images of typical glomeruli stained with periodic acid-Schiff (PAS). Glomeruli of WT-CONT (A) and HET-CONT (B) appeared normal with no differences in PAS positive staining. Glomeruli of WT-HFF mice showed glomerular hypertrophy (C) and some presented with glomerulosclerosis (D). Kidneys of HET-HFF mice contained very large glomeruli (E) and glomeruli with glomerulosclerosis (F). Bar = 100 um. Panels G-J: Fluorescent micrographs of collagen IV (Red) immunostaining. Collagen IV immunostaining in control WT (G) and HET (H) kidneys presented as a fine matrix localized to basement membranes of renal tubules, Bowmans capsule and the intra and extraglomerular mesangium. In obese WT (I) and HET (J) kidneys, the accumulation of collagen IV protein was present and localized to the tubulointerstitium associated with expansion of the interstitial space (arrow). More extensive collagen IV was also evident in the glomerulointerstitium surrounding the glomerular Bowman’s capsule.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3760915&req=5

pone-0073095-g004: Typical histological features of kidneys of wildtype (WT) and GDNF HET mice fed control (CONT) or high fat (HFF) diet.Panels A-F: High power images of typical glomeruli stained with periodic acid-Schiff (PAS). Glomeruli of WT-CONT (A) and HET-CONT (B) appeared normal with no differences in PAS positive staining. Glomeruli of WT-HFF mice showed glomerular hypertrophy (C) and some presented with glomerulosclerosis (D). Kidneys of HET-HFF mice contained very large glomeruli (E) and glomeruli with glomerulosclerosis (F). Bar = 100 um. Panels G-J: Fluorescent micrographs of collagen IV (Red) immunostaining. Collagen IV immunostaining in control WT (G) and HET (H) kidneys presented as a fine matrix localized to basement membranes of renal tubules, Bowmans capsule and the intra and extraglomerular mesangium. In obese WT (I) and HET (J) kidneys, the accumulation of collagen IV protein was present and localized to the tubulointerstitium associated with expansion of the interstitial space (arrow). More extensive collagen IV was also evident in the glomerulointerstitium surrounding the glomerular Bowman’s capsule.

Mentions: Renal histology of control HET mice was indistinguishable from control WT mice other than the presence of larger glomeruli in HET mice (Figure 4). Renal architecture of obese WT and HET mice was maintained, though they demonstrated expansion of the interstitial space and focal areas of inflammatory cell accumulation (not shown). Glomeruli of obese WT and HET mice appeared markedly larger with evidence of mesangial expansion and glomerulosclerosis (Figure 4).


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)

Typical histological features of kidneys of wildtype (WT) and GDNF HET mice fed control (CONT) or high fat (HFF) diet.Panels A-F: High power images of typical glomeruli stained with periodic acid-Schiff (PAS). Glomeruli of WT-CONT (A) and HET-CONT (B) appeared normal with no differences in PAS positive staining. Glomeruli of WT-HFF mice showed glomerular hypertrophy (C) and some presented with glomerulosclerosis (D). Kidneys of HET-HFF mice contained very large glomeruli (E) and glomeruli with glomerulosclerosis (F). Bar = 100 um. Panels G-J: Fluorescent micrographs of collagen IV (Red) immunostaining. Collagen IV immunostaining in control WT (G) and HET (H) kidneys presented as a fine matrix localized to basement membranes of renal tubules, Bowmans capsule and the intra and extraglomerular mesangium. In obese WT (I) and HET (J) kidneys, the accumulation of collagen IV protein was present and localized to the tubulointerstitium associated with expansion of the interstitial space (arrow). More extensive collagen IV was also evident in the glomerulointerstitium surrounding the glomerular Bowman’s capsule.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073095-g004: Typical histological features of kidneys of wildtype (WT) and GDNF HET mice fed control (CONT) or high fat (HFF) diet.Panels A-F: High power images of typical glomeruli stained with periodic acid-Schiff (PAS). Glomeruli of WT-CONT (A) and HET-CONT (B) appeared normal with no differences in PAS positive staining. Glomeruli of WT-HFF mice showed glomerular hypertrophy (C) and some presented with glomerulosclerosis (D). Kidneys of HET-HFF mice contained very large glomeruli (E) and glomeruli with glomerulosclerosis (F). Bar = 100 um. Panels G-J: Fluorescent micrographs of collagen IV (Red) immunostaining. Collagen IV immunostaining in control WT (G) and HET (H) kidneys presented as a fine matrix localized to basement membranes of renal tubules, Bowmans capsule and the intra and extraglomerular mesangium. In obese WT (I) and HET (J) kidneys, the accumulation of collagen IV protein was present and localized to the tubulointerstitium associated with expansion of the interstitial space (arrow). More extensive collagen IV was also evident in the glomerulointerstitium surrounding the glomerular Bowman’s capsule.
Mentions: Renal histology of control HET mice was indistinguishable from control WT mice other than the presence of larger glomeruli in HET mice (Figure 4). Renal architecture of obese WT and HET mice was maintained, though they demonstrated expansion of the interstitial space and focal areas of inflammatory cell accumulation (not shown). Glomeruli of obese WT and HET mice appeared markedly larger with evidence of mesangial expansion and glomerulosclerosis (Figure 4).

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