Question: 

Obesity is often accompanied by hyperlipidemia, insulin resistance/diabetes mellitus type 2 and arterial hypertension, which together form the Metabolic Syndrome. The nuclear receptor transcription factor Peroxisome Proliferator-Activated Receptor-gamma (PPARgamma) is the central molecular switch in the Metabolic Syndrome. We found recently that PPARgamma induces the transcription of renin gene. In addition, the hypertension during obesity is known to be renin-dependent. Therefore we aimed to study the possible role of the PPARgamma-induced increase of renin production in the pathogenesis of arterial hypertension in high-fat diet model of obesity.

Methods: 

We used mice with a specific knockout of PPARgamma in the renin-producing juxtaglomerular (JG) cells of the kidney (termed hereafter RC-PPARfl/fl mice) and their inbred wild-type controls (termed RC-PPARwt/wt). Mice from each of the two genotypes were randomized into two groups (n=6) which were fed with normal or with high-fat (20% fat) chow for 5 days. Blood pressure (tail-cuff), weight gain and food intake were monitored. At the end of the experiments Plasma Renin Concentration (PRC) was measured and the kidneys were used for isolation of total RNA and qRT-PCR.

Results: 

There were no significant changes in the weight of the animals in all four experimental groups. However, the energy intake was significantly elevated in the high-fat groups compared to the normal-diet groups of each genotype (genotype RC-PPARwt/wt 3.1±0.04 vs 2.7±0.19 kJ/g/d, p=0.038; genotype RC-PPARfl/fl 3.2±0.12 vs 2.9±0.09 kJ/g/d, p=0.046). The expression of the canonical PPARgamma-regulated gene FABP-4 was significantly up-regulated by high-fat diet in the kidneys of both genotypes, demonstrating that PPARgamma was activated. Arterial blood pressure was elevated in the RC-PPARwt/wt animals on high-fat diet compared to their normal-diet controls (131±3 vs 123±2 mmHg, p=0.02), but not in the PPARgamma-deficient RC-PPARfl/fl animals on high-fat diet compared to their normal-diet controls (120±2.5 vs 122±3 mmHg, p=0.58). PRC and renal renin mRNA expression were elevated (by about 50%) by high-fat diet also in the RC-PPARwt/wt genotype, but not in the PPARgamma-deficient RC-PPARfl/fl animals.

Conclusions: 

Our data suggest that PPARgamma is involved in the stimulation of renin expression in JG cells by high-fat diet. The PPARgamma-dependent increase of renin expression appears to play essential role in the development of arterial hypertension in the high-fat diet model of obesity.