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

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $272,500

## Abstract

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 whet...

## Key facts

- **NIH application ID:** 10020982
- **Project number:** 5R01DK121411-02
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Jussara M. Do Carmo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $272,500
- **Award type:** 5
- **Project period:** 2019-09-19 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020982

## Citation

> US National Institutes of Health, RePORTER application 10020982, Long-term consequences of parental obesity on developmental programming of cardiorenal diseases in offspring (5R01DK121411-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020982. Licensed CC0.

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