Perinatal Obesity Sensitizes for Premature Kidney Aging Signaling.
Jaco SelleKatrin BohlKatja HöpkerRebecca WilkeKatharina DingerPhilipp KasperBastian AbendBernhard SchermerRoman-Ulrich MüllerChristine E KurschatKai-Dietrich NüskenEva NüskenDavid H MeyerSoni Savai PullamsettiBjörn SchumacherJörg DötschMiguel A Alejandre AlcazarPublished in: International journal of molecular sciences (2023)
Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1 , revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.
Keyphrases
- insulin resistance
- high fat diet induced
- metabolic syndrome
- high fat diet
- weight loss
- type diabetes
- chronic kidney disease
- weight gain
- oxidative stress
- pregnant women
- dna damage
- induced apoptosis
- adipose tissue
- global health
- dna damage response
- end stage renal disease
- blood pressure
- signaling pathway
- skeletal muscle
- public health
- genome wide
- epithelial mesenchymal transition
- machine learning
- gene expression
- endoplasmic reticulum stress
- physical activity
- deep learning
- big data
- ischemia reperfusion injury
- case control
- heat stress