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

Seshini Gurusinghe,Russell D Brown,Xiaochu Cai,Sharon D Ricardo,Michelle M Kett,Chrishan S Samuel,Merlin C Thomas,David Long

doi:10.1371/journal.pone.0073095

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.

Highlights

Obesity is associated with a wide spectrum of disorders including hypertension, vascular and cardiac dysfunction, and diabetes, leading to an increased risk of cardiovascular disease
Limited studies in humans with a nephron deficit have suggested that BMI contributes to the progression of kidney disease in these individuals [1,4,5,6]
Twenty weeks of high fat feeding led to diet-induced obesity that was characterized by hyperinsulineamia, higher plasma free fatty acids (FFA) and TG, hypertension, renal hyperfiltration, albuminuria, renal injury and aberrant collagen deposition

Summary

Introduction

Obesity is associated with a wide spectrum of disorders including hypertension, vascular and cardiac dysfunction, and diabetes, leading to an increased risk of cardiovascular disease. Kidney disease in obesity was considered secondary to cardiovascular risk factors, hypertension and diabetes. A high BMI has recently been demonstrated as an independent risk factor for chronic renal disease [1,2]. Not all individuals with obesity develop hypertension or chronic kidney disease. A hypothesis emerging in the literature is that a low nephron number increases the susceptibility to obesity-induced chronic kidney disease and hypertension through greater elevations in glomerular capillary pressure and exhaustion of renal functional reserve [1,4,5,6]. The impact of obesity in the presence of a reduced nephron number has not been examined experimentally

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