Maternal High-Fat Diet Programs Renal Peroxisomes and Activates NLRP3 Inflammasome-Mediated Pyroptosis in the Rat Fetus

Abstract

Maternal obesity impairs kidney development and function of the offspring and leads to a greater risk of kidney disease in adulthood. The present study aimed to investigate the link between peroxisomes, oxidative stress (OS), and inflammasomes in the fetal kidney of maternal obesity rats and to explore the potential therapeutic effects of the antioxidant pyrroloquinoline quinone (PQQ). Methods: Maternal obesity rats were developed by administration of a high fat diet plus supplementation with PQQ (40 mg/kg body weight) as a potential therapy. Renal histology was observed by Periodic Acid-Schiff staining. The expression profiles of peroxins, fatty acid β-oxidation enzymes, antioxidants, and the regulators of the unfolded protein response (UPR) pathway and NLRP3 inflammasome were analyzed in the kidneys and tubular epithelial cells (TECs) from near-term fetuses (embryonic day 20). Results: The present work revealed that: 1) a maternal high fat diet (MHF) led to higher blood pressure in adult offspring; 2) MHF led to downregulation of peroxisome markers PEX3 and 14 in fetal kidneys; 3) the antioxidant SOD2 and catalase were decreased, and oxidative stress marker Ephx2 was increased; 4) MHF-induced activation of the UPR pathway; 5) the KEAP1-NRF2 pathway was activated; 6) activation of the NLRP3 inflammasome led to secretion of pro-inflammation factors; 7) in TECs, the changes in PEXs and NLRP3 are similar to tissues, but UPR and NRF2 pathways showed opposite trends; 8) and the antioxidant PQQ alleviated maternal lipotoxicity by decreasing ROS levels and inhibiting activation of ER stress and inflammasome in fetal kidney. Conclusion:A maternal high fat diet decreased the number of peroxisomes, subsequently activated OS and inflammasomes, resulting in pyroptosis and apoptosis in fetal kidney. The antioxidant PQQ served a protective role against the effects of lipotoxicity on kidney programming and, thus, is a potential candidate to prevent maternal obesity-induced renal programming.

Programming by maternal obesity: a pathway to poor cardiometabolic health in the offspring

“…In contrast, a study in rats has shown that exposure to maternal obesity in the late-gestation fetus did not affect fetal kidney nephron number (173) . However, there was evidence for increased cellular stress, inflammation and apoptosis in the kidney of fetuses of obese dams compared to healthy controls (173) .…”

“…In contrast, a study in rats has shown that exposure to maternal obesity in the late-gestation fetus did not affect fetal kidney nephron number (173) . However, there was evidence for increased cellular stress, inflammation and apoptosis in the kidney of fetuses of obese dams compared to healthy controls (173) . Furthermore, late-gestation proteomic analysis of male fetal mouse kidneys from dams fed with a high-fat diet showed differential expression of proteins linked to transcription/translation, mitochondrial processes and membrane remodelling compared to offspring of controls (174) .…”

Maternal obesity and offspring health: Adapting metabolic changes through autophagy and mitophagy

“…61,62 In terms of mechanism of action, maternal obesity increased apoptosis and pyroptosis in fetal kidneys, with elevated oxidative stress and decreased antioxidant defense. 63 These observations indicate that exposure to intrauterine hyperlipidemia or hyperglycemia impairs renal development and function.…”

“…149 Generally, pyroptosis is closely associated with various disorders and adverse pregnancy complications through lytic cell death, cytokines release, auto-antigens release, and dysfunction of organelles. 63,155 At present, a paucity of studies has reported the effect of pyroptosis on offspring outcomes. A recent study showed that maternal obesity reduced the number of peroxisomes and subsequently activated oxidative stress and NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated pyroptosis in fetal kidneys.…”

Diet Modification before or during Pregnancy on Maternal and Foetal Outcomes in Rodent Models of Maternal Obesity

“…Higher perinatal weights have been observed from as early as postnatal day 1, with faster weight gain, abdominal adiposity, and circulating cholesterol levels thereafter, once further challenged with an HFD [ 66 ]. Maternal obesity has been shown to increase pryoptosis and apoptosis in foetal kidneys, with decreased antioxidants such as superoxide dismutase 2 (SOD2) and catalase and increased oxidative stress marker epoxide hydrolase (Ephx) 2, mediated by the Nod-like receptor protein (NLRP) 3 inflammasome pathways [ 67 ]. Maternal obesity has also been shown to have teratogenic effects on cardiac development, with an increased risk of abnormal aortic valve development, endothelial dysfunction, and abnormal hemodynamic function in offspring [ 68 ].…”