Eva Nüsken

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with anti-inflammatory effects. However, few studies have investigated their molecular effects in the kidney. We have previously shown that intrauterine growth restriction (IUGR) can lead to aggravation of mesangioproliferative glomerulonephritis and that n-3 PUFAs can attenuate long-term effects of IUGR by reversing pro-inflammatory molecular signatures in kidney cortex. Results: The original aim of the study was to investigate the potential protective mechanisms of docosahexaenoic acid (DHA) on murine mesangial cells. However, stimulation with DHA alone led to reduced cell viability and ultimately cell death. Proteome analysis revealed significant regulation of ferroptosis-associated proteins. Increased expression of the pro-ferroptotic protein HMOX1 and decreased expression of the pro-ferroptotic proteins TFRC and ACSL4 could indicate the onset of self-protection mechanisms in ferroptosis that is already underway. Interestingly, treatment with the ferroptosis inhibitor ferrostatin-1 maintained cellular metabolic activity and prevented cell death, further supporting a role of ferroptosis in DHA-induced cytotoxicity. Consistently, DHA-treated cells exhibited pronounced lipid peroxidation while showing no relevant activation of apoptosis. Simultaneous treatment with DHA and an antioxidant cocktail significantly attenuated cell death and induced upregulation of several key anti-ferroptotic proteins, including TXNRD1 and GPX4, while pro-ferroptotic proteins such as TFRC and ASCL4 were further reduced. Conclusion: Our results provide evidence that DHA-treatment alone may have detrimental effects in susceptible cells, which could partially explain inconsistent results of clinical studies. This emphasizes the importance of a balance between pro- and anti-ferroptotic mechanisms in therapeutic strategies using n-3 PUFAs to promote kidney health.

Our review summarizes and evaluates the current state of knowledge on lipid metabolism in relation to the pathomechanisms of kidney disease with a focus on common pediatric kidney diseases. In addition, we discuss how nutrition in early childhood can alter kidney development and permanently shape kidney lipid and protein metabolism, which in turn affects kidney health and disease throughout life. Comprehensive integrated lipidomics and proteomics network analyses are becoming increasingly available and offer exciting new insights into metabolic signatures. Lipid accumulation, lipid peroxidation, oxidative stress, and dysregulated pro-inflammatory lipid mediator signaling have been identified as important mechanisms influencing the progression of minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic kidney disease, and acute kidney injury. We outline key features of metabolic homeostasis and lipid metabolic physiology in renal cells and discuss pathophysiological aspects in the pediatric context. On the one hand, special vulnerabilities such as reduced antioxidant capacity in neonates must be considered. On the other hand, there is a unique window of opportunity during kidney development, as nutrition in early life influences the composition of cellular phospholipid membranes in the growing kidney and thus affects local signaling pathways far beyond the growth phase. Graphical

Intrauterine growth restriction (IUGR) and being small for gestational age (SGA) are two distinct conditions with different implications for short- and long-term child development. SGA is present if the estimated fetal or birth weight is below the tenth percentile. IUGR can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnion, lack of growth in the interval, estimated weight below the third percentile) and can also be present in fetuses and neonates with weights above the tenth percentile. There is a need to differentiate between IUGR and SGA whenever possible, as IUGR in particular is associated with greater perinatal morbidity, prematurity and mortality, as well as an increased risk for diseases in later life. Recognizing fetuses and newborns being “at risk” in order to monitor them accordingly and deliver them in good time, as well as to provide adequate follow up care to ameliorate adverse sequelae is still challenging. This review article discusses approaches to differentiate IUGR from SGA and further increase diagnostic accuracy. Since adverse prenatal influences increase but individually optimized further child development decreases the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood. Moreover, we present current concepts of pathophysiology, with a focus on oxidative stress and consecutive inflammatory and metabolic changes as key molecular mechanisms of adverse sequelae, and look at future scientific opportunities and challenges. Most importantly, awareness needs to be raised that pre- and postnatal care of IUGR neonates should be regarded as a continuum.

Intrauterine growth restriction (IUGR) and being born small for gestational age (SGA) are two distinct conditions with different implications for child development. IUGR is associated with greater perinatal morbidity and mortality and can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnios, lack of growth in the interval, estimated weight <3rd percentile). IUGR may also be present in neonates with birth weights above the 10th percentile. Recognizing fetuses being “at risk” of a higher perinatal mortality and morbidity rate in order to monitor them accordingly and deliver them in good time is still challenging. This review article summarizes approaches to increase the diagnostic accuracy of IUGR and presents current concepts of pathophysiology with a focus on oxidative stress and consecutive inflammatory and metabolic changes. Since prenatal influences affect the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood and look at future scientific challenges. It should be emphasized that prenatal and postnatal care of IUGR neonates should be regarded as a continuum.

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.

Purpose of review: The purpose of this update is to summarize current knowledge on the pathophysiology of immunglobulin A (IgA) vasculitis nephritis (IgAVN) as well as to critically review evidence for established therapeutic regimes and available biomarkers. An additional purpose is to raise the discussion what could be done to further improve our understanding of IgAVN, identify patients at risk for adverse outcome and increase the evidence for therapy recommendations. Recent findings: Clinical and experimental studies have established the concept of a multilevel pathogenesis. Toll-like-receptor activation, B cell proliferation, micro-RNAs and complement activation have been identified or confirmed as potential therapeutic targets which can modify the course of the disease. Currently, kidney injury molecule-1, monocyte chemotactic protein-1, N-acetyl-β-glucosaminidase, and angiotensinogen are the most promising urinary biomarkers for early diagnosis of renal involvement in IgA vasculitis. Summary: Close surveillance of all IgAV patients for renal involvement is recommended. Given the multilevel pathogenesis, early treatment of even mild cases should be initiated. Further therapeutic options should be considered in case first-line therapy (mostly corticosteroids) has no effect. The evidence supporting current therapeutic regimes is predominantly based on expert opinion. Prospective studies are needed and should involve substances inhibiting B cell proliferation and complement activation.

Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by “sham” operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.