Early nutritional intervention with docosahexaenoic acid and choline to prevent susceptibility towards arterial hypertension and aggravated course of glomerulonephritis in intrauterine growth restricted rats

• Applicants: Dr. Eva Nüsken; Dr. Kai-Dietrich Nüsken
• Subject Area: Pediatric and Adolescent Medicine ; Nutritional Sciences ; Gynaecology and Obstetrics ; Nephrology ; Reproductive Medicine, Urology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437191024

Low birth weight (LBW) is highly prevalent worldwide. Intrauterine growth restriction (IUGR) is a major cause of LBW, strongly affects kidney development, and predisposes to elevated blood pressure, adverse outcome of glomerulopathies and reduced kidney function in young adulthood. The main focus of our working group is to elucidate the molecular basis of clinical sequelae after IUGR by studying three thoroughly validated IUGR rat models, i.e. low protein diet throughout pregnancy, utero-placental insufficiency by uterine vessel ligation, and intrauterine stress by sham operation, each compared to offspring of unimpaired dams. In these models, we have shown reduced kidney weight, elevated blood pressure, and aggravated Thy1.1 glomerulonephritis. On the molecular level, we have shown perinatal dysregulation of inflammatory processes and renin expression by transcriptome, qRT-PCR and protein analyses. Our second focus is to test nutritional interventions during early life to improve long-term health. Recently, we have shown that the supramolecular structure of lipids in early diet ameliorates the adverse metabolic phenotype after IUGR. A high n-6 arachidonic acid (AA) content in kidney cell membranes promotes arterial hypertension and renal inflammation, whereas increased dietary n-3 docosahexaenoic acid (DHA) supplementation reduces AA content. Thus, we now hypothesize that early life dietary supplementation of DHA and choline prevents elevation of blood pressure and mitigates the severity of glomerulonephritis in young-adult rats after IUGR by persistently reducing AA and increasing DHA content in renal cell membranes, thereby inducing a long-term anti-hypertensive and anti-inflammatory molecular shift of fatty-acid derived mediators. To investigate the influence of early dietary supplementation of DHA and choline [i.e. from postnatal day (PND) 2 to 40] on clinical and physiological outcome in young adulthood (i.e. PND 67), we will perform longitudinal measurements of telemetric blood pressure, blood and urine parameters including renin and aldosterone before and 14 days after induction of Thy1.1 glomerulonephritis. Kidney histology will include glomerulosclerosis index, capillary widening score, ED1-positive cell count and glomerular collagen deposition. To evaluate how DHA and choline modulate molecular signatures, we will perform lipidomics in renal cortex tissue, isolated glomeruli and blood, as well as proteomics in isolated glomeruli. To study the effect of DHA and choline on pathways indicated to be dysregulated by our previous analyses, we will perform western blots of central components of the toll-like-receptor, NF-kappa B, TNF, mTOR, AMPK and PPAR signaling pathways.The overarching goal of this proposal is to establish an effective and feasible re-programming strategy to prevent susceptibility towards arterial hypertension and aggravated glomerulonephritis after IUGR, and to understand underlying molecular mechanisms.

• DFG Programme: Research Grants