Does a Nephron Deficit Exacerbate the Renal and Cardiovascular Effects of Obesity?

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. 6wk-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.

Developmental cigarette smoke exposure II: Kidney proteome profile alterations in 6 month old adult offspring

“…We suggest that renal hyperfiltration and glomerular disease associated with a high-fat diet induced obesity paradigm may be exacerbated by the present model system of 'active' cigarette smoke exposure throughout early development since increased nephron count and kidney mass do not accompany visceral fat accumulation [68]. Rather, reduced nephron number and kidney mass prior to obesity may increase the susceptibility to obesity-induced renal disease [69]. We plan to test this hypothesis in future studies.…”

Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor

“…Six days after commencing the high-salt diet, a second 24-h urine sample was collected and MAP was measured for a further 3 days. Urinary concentration of sodium, osmolality, and albumin were measured to allow their rates of excretion to be determined (15).…”

Complications during pregnancy and fetal development: implications for the occurrence of chronic kidney disease

“…Histological evidence of tubular injury was also observed in I/R exposed IUGR offspring whereas I/R exposed control offspring were unaffected (79). A congenital reduction in nephron number also enhances susceptibility to renal disease in the presence of obesity or overfeeding during post-natal life (80, 81). Taken together, these studies suggest that exposure to an insult during development programs an increased susceptibility to renal injury in response to a secondary insult in later life (Figure).…”