**Background:** Hypertension remains a leading global risk factor for cardiovascular disease, and despite available treatments, its prevalence continues to rise. The Developmental Origins of Health and Disease (DOHaD) theory posits that adverse intrauterine environments—particularly maternal nutritional imbalance—can program fetal development toward adult hypertension. This review focuses on the mechanistic role of maternal nutrient intake and metabolic waste accumulation in hypertension programming, with emphasis on nutrient-sensing signaling pathways as potential therapeutic targets.
**Methods:** This is a narrative review synthesizing human observational studies and animal experimental models. Human evidence draws primarily from famine cohort studies (e.g., the Dutch famine of 1944–1945, which included 2,414 people aged 50 years, of whom 741 developed hypertension along with hyperlipidemia, obesity, and insulin resistance) and a Scottish study of 253 subjects whose mothers consumed high animal protein (>50 g/day) with low carbohydrate intake in late pregnancy, associated with elevated blood pressure at age 40. Animal evidence is derived from numerous rodent models of maternal malnutrition, including caloric restriction (30–70% of normal intake), protein restriction (6–9% protein), specific amino acid deficiencies (methionine, tryptophan), micronutrient deficiencies (salt, calcium, iron, vitamin D, zinc, folic acid, vitamins B2, B6, B12), and over-nutrition models (high sucrose, high fructose, high fat, Western diet, excessive protein, methyl-donors, salt). Maternal chronic kidney disease (CKD) models using adenine-induced uremia are also reviewed.
**Key Results:** The review identifies that diverse maternal nutritional insults converge on common downstream mechanisms. Five categories of nutrient-sensing signals are implicated: (1) Energy sensing via AMP-activated protein kinase (AMPK)—dysregulated AMPK signaling is linked to programmed hypertension, and AMPK activators (AICAR, metformin, resveratrol) can reduce blood pressure in spontaneously hypertensive rats and prevent hypertension in offspring from high-fat diet models. (2) Glucose sensing—maternal high-fructose diets cause long-term transcriptome changes in offspring kidneys, with differentially expressed genes related to fatty acid metabolism, fructose metabolism, insulin signaling, and glycolysis/gluconeogenesis. (3) Amino acid sensing via mechanistic target of rapamycin (mTOR)—placental mTOR and amino acid transporter activities are reduced in intrauterine growth restriction, a known hypertension risk factor. (4) Lipid sensing via peroxisome-proliferator activated receptors (PPARs), liver X receptors, and G-protein coupled receptors (GPR41, GPR43)—maternal high-fructose diet reduces renal GPR41 and GPR43 expression in offspring, while PPAR signaling pathways are involved in caloric restriction and high-fructose models. (5) Additional interconnected mechanisms include oxidative stress, nitric oxide deficiency, aberrant renin-angiotensin system, epigenetic regulation, increased sympathetic nerve activity, sex differences, gut microbiota dysbiosis, and impaired sodium transport.
Regarding metabolic wastes, maternal CKD (prevalence 3–4% in women of childbearing age) leads to accumulation of uremic toxins including asymmetric dimethylarginine (ADMA), trimethylamine N-oxide (TMAO), and reductions in beneficial microbiota-derived metabolites (acetate, butyrate). Maternal TMAO administration directly increases offspring blood pressure in animal models.
Reprogramming strategies evaluated include: (1) Nutritional interventions—amino acid supplementation (taurine, citrulline, glycine, cysteine, tryptophan, branched-chain amino acids), lipid supplementation (conjugated linoleic acid, omega-3 PUFAs, short-chain fatty acids acetate/butyrate/propionate), prebiotic carbohydrates (inulin), and micronutrients (folic acid, vitamins C, E, selenium). (2) Targeting nutrient-sensing signals—AMPK activators (resveratrol, metformin, AICAR, quercetin, epigallocatechin gallate, garlic) and PPAR agonists (pioglitazone, rosiglitazone, conjugated linoleic acid, omega-3 PUFAs). (3) Reduction of metabolic wastes—TMAO production inhibitors (iodomethylcholine, 3,3-dimethyl-1-butanol), ADMA-lowering agents (telmisartan, melatonin, resveratrol, N-acetylcysteine, atorvastatin, vitamin E, metformin, rosuvastatin, aliskiren), and potential aryl hydrocarbon receptor antagonists for tryptophan-derived uremic toxins.
**Clinical Implications:** The review highlights that hypertension prevention may need to begin before birth, targeting metabolic disturbances during fetal development. However, significant gaps remain between animal research and clinical application. The authors note that scarce information exists on how animal-derived reprogramming strategies might translate to pregnant women. They call for longitudinal analyses of metabolites and nutrient-sensing biomarkers to identify optimal timing and design of hypothesis-driven interventions. The prevalence of CKD in women of childbearing age (3–4%) and its link to offspring hypertension is identified as an understudied area. The review concludes that early-life interventions targeting metabolic restoration—particularly through nutrient-sensing signals and reduction of uremic toxins—could offer novel therapeutic opportunities to reduce the global hypertension burden, though specific clinical recommendations await further human studies.