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Tain, Y. Renal Programming Related to Nitric Oxide (NO) Pathway. Encyclopedia. Available online: https://encyclopedia.pub/entry/20038 (accessed on 09 February 2026).
Tain Y. Renal Programming Related to Nitric Oxide (NO) Pathway. Encyclopedia. Available at: https://encyclopedia.pub/entry/20038. Accessed February 09, 2026.
Tain, You-Lin. "Renal Programming Related to Nitric Oxide (NO) Pathway" Encyclopedia, https://encyclopedia.pub/entry/20038 (accessed February 09, 2026).
Tain, Y. (2022, March 01). Renal Programming Related to Nitric Oxide (NO) Pathway. In Encyclopedia. https://encyclopedia.pub/entry/20038
Tain, You-Lin. "Renal Programming Related to Nitric Oxide (NO) Pathway." Encyclopedia. Web. 01 March, 2022.
Renal Programming Related to Nitric Oxide (NO) Pathway
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This entry is adapted from the peer-reviewed paper 10.3390/ijms20030681

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. 

kidney disease nitric oxide

1. Oxidatice Stress

Oxidative stress is an imbalance between pro-oxidant molecules and antioxidant defenses, mainly related to dysregulation of reactive oxygen species (ROS) and NO. The developing fetus is highly vulnerable to oxidant injury due to its low antioxidant capacity [1]. Thus, early-life NO–ROS imbalance is capable of programming adult hypertension and kidney disease [2][3]. Cumulative evidence indicates that a variety of prenatal insults lead to renal programming and hypertension associated with oxidative stress, including maternal undernutrition [4], maternal diabetes [5], prenatal glucocorticoid administration [6][7][8], preeclampsia [9], and exposure to high-fructose diet [10] and high-fat diet [11] in pregnancy and lactation. Importantly, among these programmed models, the impaired l-arginine–ADMA–NO pathway is closely interrelated to oxidative stress in determining the programming process as we reviewed elsewhere [12].
NO depletion in pregnancy induced by NG-nitro-l-arginine-methyl ester (l-NAME, an inhibitor of NOS) caused renal programming, increased oxidative stress, and programmed hypertension in adult offspring [13][14]. Additionally, maternal NO deficiency alters a wide range of signaling pathways as found by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis [15]. Among them, the mitogen-activated protein kinases (MAPK) pathway is involved in redox-sensitive signaling, contributing to the development of hypertension [16]. Furthermore, our previous report showed that NO deficiency in embryonic kidneys (metanephroi) induced by ADMA impairs nephrogenesis [17]. Metanephroi grown in 2 or 10 µM ADMA were significantly smaller and contained fewer nephrons in a dose-dependent manner [17]. Metanephroi grown in 10 µM ADMA altered a total of 1221 differential expressed genes by next-generation RNA sequencing (NGS) analysis [18]. Among them, Avpr1a, Ephx2, Hba2, Hba-a2, and Npy1r have been identified as differentially expressed genes in the kidney in different programmed hypertension models [15][17][18][19]. Thus, results from these studies suggest a link between NO deficiency and oxidative stress in the developmental programming of hypertension and kidney disease. The arrow means produces, indicating result of reaction. The T-bar means inhibits.

2. Renin-Angiotensin System

The role of RAS in mediating kidney development and regulating BP has received considerable attention [20][21]. Pharmacological blockade of the RAS has been clinically used as the first choice for hypertension and renal protection. This system consists of different angiotensin peptides mediated by distinct receptors. The classic RAS, defined as the angiotensin converting enzyme (ACE)-angiotensin (Ang) II-angiotensin type 1 receptor (AT1R) axis, promotes vasoconstriction and sodium retention. Conversely, the non-classical RAS composed of the ACE2-Ang-(1-7)-Mas receptor axis leads to vasodilatation [21]. The RAS have been reported to be associated with developmental programming of hypertension in a variety of models, including prenatal glucocorticoid administration [6][7][8], high-fat diet [11], low-protein diet [22], high-sucrose diet [23], and high-fructose diet [24]. NO inhibition by L-NAME in pregnancy caused programmed hypertension in adult offspring, which was associated with increased mRNA of renin and ACE in offspring kidney [14]. On the other hand, blockade of the classical RAS between 2–4 weeks of age has been reported to prevent the developmental programming of hypertension [24][25][26][27]. These protective effects are not only directed upon the RAS, but also through regulating the NO system. In spontaneously hypertensive rat (SHR), early therapy with aliskiren, a renin inhibitor, has been reported to reduce ADMA, restore l-arginine-to-ADMA ratio, and increase renal cortical nNOS protein level to prevent the development of hypertension [28]. Similarly, early aliskiren therapy protects adult rat offspring exposed to maternal caloric restriction against programmed hypertension via ADMA reduction [27]. Nevertheless, the detailed mechanisms underlying the interplay between the RAS and NO pathway contributing to the programmed hypertension and kidney disease need to be further investigated.

3. Nutrient-Sensing Signals

Nutrient-sensing signals play a crucial role in fetal metabolism and development. Imbalanced nutrition and metabolic status during pregnancy can disturb nutrient-sensing signals, resulting in renal programming and developmental hypertension [12][28]. Several well-known nutrient-sensing signaling pathways exist in the kidney, including cyclic adenosine monophosphate (AMP)-activated protein kinase (AMPK), silent information regulator transcript (SIRT), peroxisome proliferator-activated receptors (PPARs), and PPARγ coactivator-1α (PGC-1α) [29]. The interplay between AMPK and SIRTs, driven by maternal nutritional interventions were found to regulate PPARs and their target genes, thereby driving a programmed process of hypertension [12][30]. Among the PPAR target genes [31], Nos2, Nos3, Sod2, and Nrf2 are related to NO pathway and oxidative stress. AMPK, SIRT1, and PGC-1α can also promote autophagy, a lysosome-mediated degradation process for damaged cellular constituents [32]. Since eNOS-derived NO is capable to activate PGC-1α via AMPK to regulate mitochondrial biogenesis [33], the interplay between NO and nutrient-sensing signals tightly controls the mitochondrial lifecycle (mitochondrial biogenesis vs. removal by autophagy) [34].
AMPK activators and PPAR modulators have been proposed as reprogramming strategies for programmed hypertension and kidney disease [30][35]. Using a combined maternal plus post-weaning high-fat diet model, we found that resveratrol, an AMPK activator, prevents the two-hit induced hypertension and increases protein levels of SIRT1, AMPK2α, and PGC-1α in the offspring kidney [36]. Also, resveratrol reduces renal ADMA concentration as well as oxidative stress damage. These results provide evidence for the contribution of nutrient-sensing signals in renal programming and thus for the development programming of hypertension.

4. Sex Differences

Sex differences in the developmental programming of kidney disease and hypertension have been reported [37][38][39], showing that males are more vulnerable than females. Indeed, several common mechanisms of renal programming, such as the oxidative stress [40], RAS [41] and nutrient-sensing signal [42] have been documented a sex-specific response to environmental insults. The renal transcriptome in response to early-life stimuli is also sex-specific [24][43][44]. Our previous report documented that maternal high-fructose diet induced sex-specific alterations of renal transcriptome [24]. At one week of age, maternal high-fructose consumption caused greater changes of renal transcriptome in female offspring than male offspring [24]. Our finding is in agreement with another study showing that more genes in the placenta were affected in females than in males under different maternal diets [45]. Whether the increased female sensitivity to maternal diet might buffer the deleterious programming effects to protect the female fetuses, leading to a better adaptation and less impact of programmed hypertension and kidney disease in adulthood awaits further evaluation. It is noteworthy that NO production is better preserved in females than in males [46]. The mechanisms responsible for these sex differences in programmed hypertension and kidney disease are not well understood. Thus, better understanding of the impact of NO system on sex-dependent mechanisms that underlie renal programming will aid in developing novel sex-specific strategies to prevent programmed kidney disease and hypertension in both sexes.

5. Others

There are other potential mechanisms related to renal programming by which NO signaling might act: (1) sodium transporters, (2) epigenetic regulation, and (3) gut microbiota. First, hypertension and kidney disease have been associated with increased expression/activity of sodium transporters and enhanced sodium reabsorption [47][48]. NO has an inhibitory effect on the activity of several sodium transporters [49]. Thus, it is speculated that NO deficiency may fail to counterbalance the impaired sodium transporters induced by early-life insults, thus leading to programmed hypertension. Next, epigenetic regulation such as histone modifications, DNA methylation, and non-coding RNAs are involved in developmental programming [50]. Histone deacetylases have been reported to epigenetically regulate several genes belonging to the RAS [51]. Although NO has been considered as an epigenetic modulator, the epigenetic effects of NO on the aforementioned mechanisms have not been pursued in animal models of development programming to any great extent. Moreover, emerging evidence documents that the development of hypertension is correlated with gut microbiota dysbiosis [52][53]. Of note, inhibition of NO is proposed as a potential mechanism linking dysbiosis and hypertension [52].

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