Mechanisms of renal disease progression in offspring from obese parents - obesity is a major risk factor for hypertension and chronic kidney disease (CKD), and accumulating evidence indicates that…

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of Mississippi Medical Center $350,000 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate mechanisms by which parental obesity programs macrophage immunometabolism and increases offspring susceptibility to acute kidney injury and chronic kidney disease progression.

The research determines how parental obesity alters macrophage phenotype and metabolism during acute kidney injury and aging-related kidney dysfunction; establishes the contribution of macrophage P2X7R (purinergic receptor) activation to renal inflammation and injury; and evaluates whether targeting macrophage metabolism by reducing glycolysis and promoting oxidative metabolism improves kidney repair and limits chronic kidney disease progression. Preliminary studies demonstrate that offspring from obese parents exhibit early renal dysfunction, heightened kidney inflammation, increased P2X7R expression, and altered macrophage immunometabolism even on a normal diet. Genetic deletion of P2X7R, including in macrophages, attenuates renal inflammation and injury following acute kidney injury, suggesting that excessive P2X7R activation contributes to maladaptive inflammatory responses in this population.

Performance occurs in Mississippi with a period of performance from September 1, 2026, through April 30, 2030.

Mechanisms of renal disease progression in offspring from obese parents - obesity is a major risk factor for hypertension and chronic kidney disease (CKD), and accumulating evidence indicates that parental obesity increases the susceptibility of offspring to cardiorenal disease. Our preliminary studies demonstrate that offspring from obese parents exhibit early renal dysfunction, heightened kidney inflammation, increased expression of the purinergic receptor P2X7 (P2X7R), and altered macrophage immunometabolism, even when maintained on a normal diet. We also found that genetic deletion of P2X7R, including in macrophages, attenuates renal inflammation and injury following acute kidney injury (AKI), suggesting that excessive P2X7R activation contributes to maladaptive inflammatory responses in offspring from obese parents. The overall objective of this project is to determine the mechanisms by which parental obesity programs macrophage immunometabolism to increase susceptibility to acute kidney injury (AKI) and aging-related CKD. We hypothesize that excessive P2X7R activation and altered macrophage metabolism promote a pro-inflammatory macrophage phenotype that impairs kidney repair following AKI and accelerates progression to CKD. To test this hypothesis, we will (1) determine how parental obesity alters macrophage phenotype and metabolism during AKI and aging-related kidney dysfunction; (2) determine the contribution of macrophage P2X7R activation to renal inflammation and injury; and (3) determine whether targeting macrophage metabolism by reducing glycolysis and promoting oxidative metabolism improves kidney repair and limits CKD progression.