Asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) are toxic, non-proteinogenic amino acids formed by post-translational modification and are uremic toxins that inhibit nitric ...oxide (NO) production and play multifunctional roles in many human diseases. Both ADMA and SDMA have emerged as strong predictors of cardiovascular events and death in a range of illnesses. Major progress has been made in research on ADMA-lowering therapies in animal studies; however, further studies are required to fill the translational gap between animal models and clinical trials in order to treat human diseases related to elevated ADMA/SDMA levels. Here, we review the reported impacts of ADMA and SDMA on human health and disease, focusing on the synthesis and metabolism of ADMA and SDMA; the pathophysiological roles of these dimethylarginines; clinical conditions and animal models associated with elevated ADMA and SDMA levels; and potential therapies against ADMA and SDMA. There is currently no specific pharmacological therapy for lowering the levels and counteracting the deleterious effects of ADMA and SDMA. A better understanding of the mechanisms underlying the impact of ADMA and SDMA on a wide range of human diseases is essential to the development of specific therapies against diseases related to ADMA and SDMA.
Maternal nutrition plays a decisive role in developmental programming of many non-communicable diseases (NCDs). A variety of nutritional insults during gestation can cause programming and contribute ...to the development of adult-onset diseases. Nutritional interventions during pregnancy may serve as reprogramming strategies to reverse programming processes and prevent NCDs. In this review, firstly we summarize epidemiological evidence for nutritional programming of human disease. It will also discuss evidence from animal models, for the common mechanisms underlying nutritional programming, and potential nutritional interventions used as reprogramming strategies.
The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, ...resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.
Scope
Alterations of gut metabolites, such as SCFAs and trimethylamine (TMA), and microbial composition are associated with the development of hypertension. Whether maternal 3,3‐dimethyl‐1‐butanol ...(DMB, an inhibitor for TMA formation) treatment or the predominant SCFA acetate supplementation can prevent programed hypertension induced by a high‐fructose diet (HFD) exposure during pregnancy and lactation in adult male offspring is examined.
Methods and results
Male offspring are divided into four groups: ND, normal diet; HFD, 60% HFD; ACE, HFD plus 200 mmol L–1 magnesium acetate in drinking water; and DMB: HFD plus 1% DMB in drinking water. Maternal HFD induces programed hypertension in adult male offspring, which is prevented by maternal acetate supplementation or DMB treatment. HFD‐induced hypertension is relevant to increased plasma levels of TMA and acetate, and alterations of gut microbial composition. The protective effects of acetate supplementation are associated with decreased plasma TMA level and TMA‐to‐trimethylamine‐N‐oxide (TMAO) ratio, and increased renal expression of SCFA receptors. Maternal DMB treatment reduces plasma TMA, TMAO, acetate, and propionate levels.
Conclusion
Early intervention targeting on gut‐microbiota‐derived metabolites TMAO and SCFAs to reprogram hypertension may have significant impact to reduce the burden of hypertension.
Maternal high‐fructose diet (HFD) induces developmental programing of hypertension in adult offspring, which is associated with alterations of gut microbiota compositions and their metabolites: trimethylamine (TMA), trimethylamine‐N‐oxide (TMAO), and SCFAs. 3,3‐Dimethyl‐1‐butanol (an inhibitor for TMA formation) or the predominant SCFA acetate supplementation can prevent maternal HFD‐induced programed hypertension.
Development of the kidney can be altered in response to adverse environments leading to renal programming and increased vulnerability to the development of hypertension and kidney disease in ...adulthood. By contrast, reprogramming is a strategy shifting therapeutic intervention from adulthood to early life to reverse the programming processes. Nitric oxide (NO) is a key mediator of renal physiology and blood pressure regulation. NO deficiency is a common mechanism underlying renal programming, while early-life NO-targeting interventions may serve as reprogramming strategies to prevent the development of hypertension and kidney disease. This review will first summarize the regulation of NO in the kidney. We also address human and animal data supporting the link between NO system and developmental programming of hypertension and kidney disease. This will be followed by the links between NO deficiency and the common mechanisms of renal programming, including the oxidative stress, renin⁻angiotensin system, nutrient-sensing signals, and sex differences. Recent data from animal studies have suggested that interventions targeting the NO pathway could be reprogramming strategies to prevent the development of hypertension and kidney disease. Further clinical studies are required to bridge the gap between animal models and clinical trials in order to develop ideal NO-targeting reprogramming strategies and to be able to have a lifelong impact, with profound savings in the global burden of hypertension and kidney disease.
The concept that hypertension and chronic kidney disease (CKD) originate in early life has emerged recently. During pregnancy, tryptophan is crucial for maternal protein synthesis and fetal ...development. On one hand, impaired tryptophan metabolic pathway in pregnancy impacts fetal programming, resulting in the developmental programming of hypertension and kidney disease in adult offspring. On the other hand, tryptophan-related interventions might serve as reprogramming strategies to prevent a disease from occurring. In the present review, we aim to summarize (1) the three major tryptophan metabolic pathways, (2) the impact of tryptophan metabolism in pregnancy, (3) the interplay occurring between tryptophan metabolites and gut microbiota on the production of uremic toxins, (4) the role of tryptophan-derived metabolites-induced hypertension and CKD of developmental origin, (5) the therapeutic options in pregnancy that could aid in reprogramming adverse effects to protect offspring against hypertension and CKD, and (6) possible mechanisms linking tryptophan metabolism to developmental programming of hypertension and kidney disease.
Scope
Perinatal high‐fat (HF) diet induces hypertension in adult offspring. Garlic, a naturally dietary source of Hydrogen sulfide (H2S) donor, has been shown benefits in hypertension. The article ...examines whether maternal garlic oil supplementation can prevent hypertension induced by HF diet and elucidate its protective effects.
Methods and results
Pregnant rats are given either a normal diet or HF diet. Rat dams are given garlic oil or vehicle daily by oral gavage at 100 mg kg‐1 day‐1 during pregnancy and lactation. Male offspring are sacrificed at 16 weeks of age. Garlic oil supplementation during pregnancy and lactation protected against hypertension induced by HF diet in adult male offspring. The beneficial effects of garlic oil are associated with increased renal mRNA expression and activity of H2S‐generating enzymes, increased NO bioavailability, increased plasma short chain fatty acid levels, and alterations of gut microbiota composition. Garlic oil supplementation increases abundance of genus Lactobacillus, but decreases genera Turicibacter and Staphylococcus.
Conclusion
The data reveals associations between H2S‐generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota‐derived metabolites in hypertension induced by HF intake and provide insight to garlic oil as a hypertension reprogramming strategy for further translational research.
Perinatal high‐fat (HF) diet induces developmental programming of hypertension in adult offspring, which is associated with impaired hydrogen sulfide (H2S)‐generating pathway in the kidneys and gut, alterations of gut microbiota compositions and their metabolites, and reduced nitric oxide (NO). Garlic oil (a H2S donor) supplementation during pregnancy and lactation can prevent HF‐induced hypertension in adult offspring.
The gut-kidney interaction implicating chronic kidney disease (CKD) has been the focus of increasing interest in recent years. Gut microbiota-targeted therapies could prevent CKD and its ...comorbidities. Considering that CKD can originate in early life, its treatment and prevention should start in childhood or even earlier in fetal life. Therefore, a better understanding of how the early-life gut microbiome impacts CKD in later life and how to develop ideal early interventions are unmet needs to reduce CKD. The purpose of the current review is to summarize (1) the current evidence on the gut microbiota dysbiosis implicated in pediatric CKD; (2) current knowledge supporting the impact of the gut-kidney axis in CKD, including inflammation, immune response, alterations of microbiota compositions, short-chain fatty acids, and uremic toxins; and (3) an overview of the studies documenting early gut microbiota-targeted interventions in animal models of CKD of developmental origins. Treatment options include prebiotics, probiotics, postbiotics, etc. To accelerate the transition of gut microbiota-based therapies for early prevention of CKD, an extended comprehension of gut microbiota dysbiosis implicated in renal programming is needed, as well as a greater focus on pediatric CKD for further clinical translation.
Scope
High‐fructose (HF) intake, oxidative stress, nutrient‐sensing signals, and gut microbiota dysbiosis are closely related to the development of hypertension. It was investigated whether ...resveratrol can prevent hypertension induced by maternal plus post‐weaning HF diets in adult offspring via the above‐mentioned mechanisms.
Methods and results
Female Sprague‐Dawley rats received either a normal (ND) or 60% high‐fructose (HF) diet during gestation and lactation. Male offspring were assigned to five groups (maternal diet/post‐weaning diet; n = 8 per group): ND/ND, ND/HF, HF/ND, HF/HF, and HF/HF+ Resveratrol. Resveratrol (50 mg L−1) was administered in drinking water from weaning to 3 months of age. It was found that HF/HF induced hypertension in adult offspring. Maternal HF diet altered gut microbiota composition in adult offspring, including decreasing the abundance of genera Bacteroides, Dysgonomonas, and Turicibacter, while increasing phylum Verrucomicrobia and Akkermansia muciniphila. Additionally, HF/HF diets increased oxidative stress and decreased renal mRNA expression of Prkaa2, Prkag2, Ppara, Pparb, Ppargc1a, and Sirt4. Resveratrol reduced renal oxidative stress, activated nutrient‐sensing signals, modulated gut microbiota, and prevented associated HF/HF‐induced programmed hypertension.
Conclusion
Targeting oxidative stress, nutrient‐sensing signals, and gut microbiota by resveratrol might be a useful therapeutic strategy for the treatment of hypertension induced by excessive consumption of fructose in the adult rat offspring.
Maternal and post‐weaning high‐fructose diets induce developmental programming of hypertension in adult offspring, which is related to oxidative stress, nutrient‐sensing signals, and gut microbiota. Resveratrol might be a reprogramming strategy to prevent programmed hypertension induced by widespread consumption of food containing high fructose in pregnant mothers and their children.
Maternal high-fat (HF) diet is believed to induce oxidative stress and activate nutrient-sensing signals, which increase the risk of adult offspring to develop hypertension. We investigated whether ...resveratrol prevents the combined maternal plus postweaning HF-diets-induced hypertension in adult male offspring, with a focus on the kidney. Female Sprague–Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for 5 weeks before mating and during gestation and lactation. The male offspring were placed on either the ND or HF diet from weaning to 4 months of age, resulting in four experimental groups (maternal diet/postweaning diet; n=8–10/group): ND/ND, ND/HF, HF/ND and HF/HF. Another group of HF/HF rats (n=10) was treated with 0.5% resveratrol in drinking water between 2 and 4 months of age (HF/HF+R). Rats were killed at 4 months of age. We found that HF/HF-induced hypertension in adult offspring was prevented by resveratrol. Resveratrol mediated its protective effect on HF/HF-induced hypertension in the kidneys of male offspring by diminishing oxidative stress; reducing renal asymmetric dimethylarginine levels; mediating the renin–angiotensin system (RAS) in favor of vasodilatation; restoring nutrient-sensing pathways via increased levels of silent information regulator transcript 1 (SIRT1), AMP-activated protein kinase 2α and peroxisome proliferator-activated receptor gamma coactivator 1-α; and inducing autophagy. Our data implicated an association between oxidative stress, RAS, nitric oxide, and nutrient-sensing signals in HF/HF-induced hypertension. Resveratrol, acting as an antioxidant as well as a SIRT1 activator, might be a therapeutic approach for hypertension.
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