Parental obesity exacerbates immunometabolism and renal dysfunction in offspring exposed to acute kidney injury

Abstract

Kidney disease is estimated to occur in 37 million people in the US, approximately 15% of the adult population. Obesity is a major driver of kidney disease via mechanisms that are still unclear, and pre-conception obesity in the parents may program kidney dysfunction and inflammation in their offspring. Using a model of parental obesity where male and female mice are fed high fat (H) diet prior to mating, with dams maintained on the H diet during gestation and lactation, we found that male offspring exhibit hypertension and initial signs of kidney injury in adulthood (24 weeks of age). We examined whether offspring from obese parents exhibit worse outcome after acute kidney injury (AKI), and whether this is associated with an immunometabolic shift in macrophages (Mɸ) toward glycolytic and pro-inflammatory phenotypes, as assessed by flow cytometry and Seahorse extracellular flux analysis to measure extracellular acidification rate (ECAR) as a measure of glycolysis. The following groups of male mice were submitted to bilateral renal AKI by clamping the left and right pedicles for 30 min: 1) lean offspring fed normal (N) diet born from N diet lean parents (NN, n=5); 2) obese offspring fed H diet born from N diet parents (NH, n=6); 3) lean offspring fed N diet born from H diet obese parents (HN, n=6); and 4) obese offspring fed H diet born from H diet obese parents (HH, n=7). Compared to NH and NN offspring from lean parents, HH and HN offspring from obese parents exhibited worse kidney dysfunction with higher urinary renal osteopontin (OPN) levels (93.8±8.7 and 73.7±16.6 vs. 213.8±24.0 and 151.1±24.6 μg/24h). We also found increased CD45+ Mɸ-like cells which play a role in initiating and maintaining kidney inflammation, as well as worse kidney injury score, increased tubular cell death, tubular blood clot, and glomerular tubularization in offspring from obese parents. Additionally, HH and HN offspring exhibited expansion of renal M1 Mɸ phenotype 4 days after AKI assessed by ECAR (glycolysis: 5.9±0.8 and 4.1±0.5 vs. 9.5±0.9 and 13.5±0.8 ΔmpH/min). Thus, parental obesity is associated with a shift towards M1 inflammatory Mɸ phenotype and increased risk of worse renal dysfunction in their offspring after AKI, even when offspring remain lean. NIDDK 1R01121411, NIGMS P20GM104357 and NIGMS U54GM115428) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.