Long-term consequences of parental obesity on developmental programming of cardiorenal diseases in offspring

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SUMMARY/ABSTRACT Obesity is a major independent risk factor for hypertension and diabetes which, in turn, are leading causes of chronic kidney disease (CKD) and its progression to end stage renal disease (ESRD). The prevalence of obesity increased dramatically during the last few decades. Such rapid increase cannot be explained by changes in genotype, but may result from environmental factors and their interactions with genes. Maternal obesity is associated with a greater risk of hypertension in offspring and influences long-term energy balance. Although considerable effort has been devoted to investigating genetic bases of cardiovascular diseases (CVD), limited evidence is available on transgenerational non-genomic causes of cardiorenal diseases. Acute and CKD are growing worldwide and in the United States the incidence of ESRD, in particular diabetic nephropathy, has risen in parallel with increasing obesity and associated metabolic disorders. This rise in ESRD is projected to escalate further due to aging of the population. Understanding the risks of current Western lifestyle on future generations is crucial to determine potential interventions to prevent acute and CKDs and may provide insights into the mechanisms by which fetal programming influences the development of cardiorenal diseases. One potential mechanism mediating the effects of obesity-induced developmental programming on cardiorenal function is through excessive activation of the P2X purinoceptor 7 (P2X7R). P2X7R is a protein encoded by the P2X7 gene that belongs to the family of purinoceptors for ATP and its activation triggers an influx of Ca2+, cytosolic Ca2+ overload, endoplasmic reticulum (ER) stress and cytotoxicity. In addition, mitochondrial dysfunction is involved in P2X7R-mediated cell death. P2X7R may also play a key role in inflammation and several renal disease models. Using a model of maternal obesity induced via high fat feeding, we found that P2X7R expression is significantly greater in kidneys of offspring from obese parents, suggesting its potential role in the kidney injury observed in transgenerational obesity combined with hypertension (HT). We also found enhanced levels of ER stress markers and mitochondrial dysfunction in kidneys of offspring from obese parents.To determine a potential link between obesity-induced developmental programming and kidney injury, mice fed a high fat diet four weeks prior to mating, during gestation and lactation will be used to create first and second generation models of obesity. Therefore, the central hypothesis of this proposal is that developmental programming of obesity and its associated metabolic abnormalities lead to activation of P2X7R and amplification of oxidative stress and kidney injury, especially when combined with HT. These combined effects of obesity related metabolic abnormalities and HT on kidney injury are mediated by ER stress, mitochondrial dysfunction, and apoptosis. The proposed studies will determine whether first and second generation of obese parents are more susceptible to metabolic dysfunction and HT-induced kidney injury and the mechanisms responsible, which may lead to better therapeutic approaches to prevent kidney dysfunction in future generations.