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We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout (KO) mice and Akita mice treated with trigonelline (a...
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... containing rat Agt gene promoter (N-1495/N+18) and rat Ace2 gene promoter (N-1091/+83) has been described previously (17,18). The rat ACE gene promoter (N-1675/+95) and the rat MasR gene promoter (N-1811/+100) were cloned from rat genomic DNA with specific primers (Table 2) and then inserted into pGL4.20 plasmid at Bgl II/Xho I restriction sites. Scrambled (Scr) Silencer Negative Control #1 and Nrf2 small interfering RNAs (siRNAs) were obtained from Ambion, Inc. (Austin, TX). ...
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... Nrf2, Keap1, NQO-1, Agt, ACE, Ace2, MasR, and b-actin messenger RNA (mRNA) levels were quantified by realtime quantitative polymerase chain reaction (RT-qPCR) with forward and reverse primers (Table 2) (5,6,17,18,26). ...
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... containing rat Agt gene promoter (N-1495/N+18) and rat Ace2 gene promoter (N-1091/+83) has been described previously (17,18). The rat ACE gene promoter (N-1675/+95) and the rat MasR gene promoter (N-1811/+100) were cloned from rat genomic DNA with specific primers (Table 2) and then inserted into pGL4.20 plasmid at Bgl II/Xho I restriction sites. Scrambled (Scr) Silencer Negative Control #1 and Nrf2 small interfering RNAs (siRNAs) were obtained from Ambion, Inc. (Austin, TX). ...
Citations
... A clinical study of the systemic Nrf2 activator bardoxolone methyl administration to the patients with type 2 diabetes and stage-4 chronic kidney disease found increased risk of death from cardiovascular abnormalities (de Zeeuw, Akizawa et al. 2013). Nrf2 activation by oltipraz in pre-clinical rodent model induced systemic hypertension and kidney injury (Zhao, Ghosh et al. 2018). Activation of Nrf2 may have a role in carcinogenesis (Dinkova-Kostova and Copple 2023). ...
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or “chemobrain”. Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug 1c which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and 1c both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by 1c has the potential to diminish unwanted effects of fumarates while retaining efficacy.
... TRG shows various beneficial roles in many pathological conditions. It can (1) modulate glucose and lipid homeostasis [4][5][6][7][8][9][10] (A); (2) suppress the inflammatory response and oxidative stress [11][12][13][14] (B,H,M); (2) facilitate recovery from neurological impairments such as neurodegenerative disorders [15][16][17][18], ischemia-induced brain damage [19,20], cognitive decline [21][22][23], diabetic peripheral neuropathy [24,25], depression, and epilepsy [26][27][28] (C); (3) mitigate DM and its complications [6,11,[29][30][31][32] (A-F); (4) alleviate cellular injuries in the cardiovascular system [33,34], liver [35,36], kidney [37][38][39][40][41][42], gastric system [43,44], and skin [45][46][47] (D-F,I-L); and (5) inhibit proliferation and migration of tumor cells [48][49][50] (G). ↑, Increasing; ↓, decreasing.. ...
... (accessed on 29 December 2023). (2) suppress the inflammatory response and oxidative stress [11][12][13][14] (B,H,M); (2) facilitate recovery from neurological impairments such as neurodegenerative disorders [15][16][17][18], ischemia-induced brain damage [19,20], cognitive decline [21][22][23], diabetic peripheral neuropathy [24,25], depression, and epilepsy [26][27][28] (C); (3) mitigate DM and its complications [6,11,[29][30][31][32] (A-F); (4) alleviate cellular injuries in the cardiovascular system [33,34], liver [35,36], kidney [37][38][39][40][41][42], gastric system [43,44], and skin [45][46][47] (D-F,I-L); and (5) inhibit proliferation and migration of tumor cells [48][49][50] (G). ↑, Increasing; ↓, decreasing. ...
... Genetic deletion of Nrf2 or TRG inhibition of Nrf2 in diabetic Akita mice attenuated hypertension, renal injury, tubulointerstitial fibrosis, and the urinary albumin/creatinine ratio. In cultured IRPTCs, Nrf2 siRNA or TRG prevented the high glucose-induced Nrf2 nuclear translocation and expression of angiotensinogen (Agt) and angiotensin-converting enzyme (ACE), with transcriptional augmentation of ACE2 and angiotensin 1-7 (Ang 1-7) receptor [42]. ...
Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.
... highlighted because the deletion of Nrf2 during diabetic nephropathy in mice ameliorates tubulointerstitial fibrosis and renal damage. 123 In addition, Nrf2 induction may exacerbate proteinuria during CKD; hence, in glomerular diseases, Nrf2 activation is not suggested. 124 In contrast, nonproteinuric kidney diseases such as AKI and UUO could be prevented by Nrf2 activation. ...
Kidney diseases are a growing health problem worldwide, causing millions of deaths. Acute kidney injury (AKI) commonly evolves into chronic kidney disease (CKD) and fibrosis, which is a feature of CKD predisposing to end-stage renal disease. Thus, treatments that avoid this transition are urgently necessary. Mitochondria are the hub energy house of the renal cells, which provides energy in adenosine triphosphate (ATP) form, commonly obtained from β-oxidation through fatty acids degradation into the mitochondrial matrix. Mitochondria are plastic organelles that constantly change according to the cell's energy requirements. For this, mitochondria carry out biogenesis, fission, fusion, and mitophagy/autophagy, processes highly regulated to maintain mitochondrial bioenergetics and homeostasis. Alterations in one or more of these processes might cause detrimental consequences that affect cell function. In this sense, it is widely accepted that mitochondrial dysfunction associated with oxidative stress plays a crucial role in developing kidney diseases. Therefore, antioxidants that target mitochondria might be an excellent strategy to ameliorate mitochondrial dysfunction, and selecting one or another antioxidant could depend on AKI or CKD requirements. This review focuses on potent antioxidants such as sulforaphane (SFN), N-acetyl cysteine (NAC), resveratrol, curcumin, quercetin, and α-mangostin in the improvement of mitochondrial function in kidney pathologies.
... Unlike wild-type mice, these hypomorphic mice also had defects in blood pressure dipping during sleep when challenged with chronic angiotensin II infusion (Rush et al., 2021). In agreement with this, genetic Nrf2 deletion or pharmacologic inhibition lowered systolic blood pressure in mice (Zhao et al., 2018). ...
The role of NRF2 in kidney biology has received considerable interest over the past decade. NRF2 transcriptionally controls genes responsible for cellular protection against oxidative and electrophilic stress and has anti‐inflammatory functions. NRF2 is expressed throughout the kidney and plays a role in salt and water handling. In disease, animal studies show that NRF2 protects against tubulointerstitial damage and reduces interstitial fibrosis and tubular atrophy, and may slow progression of polycystic kidney disease. However, the role of NRF2 in proteinuric glomerular diseases is controversial. Although the NRF2 inducer, bardoxolone methyl (CDDO‐Me), increases glomerular filtration rate in humans, it has not been shown to slow disease progression in diabetic kidney disease and Alport syndrome. Furthermore, bardoxolone methyl was associated with negative effects on fluid retention, proteinuria, and blood pressure. Several animal studies replicate findings of worsened proteinuria and a more rapid progression of kidney disease, although considerable controversy exists. It is clear that further study is needed to better understand the effects of NRF2 in the kidney. This review summarizes the available data to clarify the promise and risks associated with targeting NRF2 activity in the kidney.
... In the presence of oxidative stress, Nrf2 is released from Keap1. Nrf2 translocates to the nucleus and binds to the antioxidant-response element (ARE) to activate the transcription of antioxidant enzymes such as SOD, CAT, HO-1, GPx, and glutathione synthetase (GS) [31,32]. Inhibiting Nrf2-mediated transcription raises the vulnerability of dopaminergic neurons to oxidative stress [33]. ...
... The data on gene expression was presented in fold-difference relatives, which were then calculated using the 2 −∆∆Ct method [41]. The following primers were used and synthesized by Macrogen (Seoul, Republic of Korea); GAPDH 5 ′ -AAC ACA GTC CAT GCC ATC AC-3 ′ (sense) and 5 ′ -TCC ACC ACC CTG TTG CTG TA-3 ′ (antisense); IL-1β 5 ′ -GAC AGC AAG TGA TAG GCC-3 ′ (sense) and 5 ′ -CGT CGG CAA TGT ATG TGT TGG-3 ′ (antisense); iNOS 5 ′ -AGA AGG AAA TGG CTG CAG AA-3 ′ (sense) and 5 ′ GCT CGG CTT CCA GTA TTG AG-3 ′ (antisense) [42]; Nrf2 5 ′ -CAG TGC TCC TAT GCG TGA A-3 ′ (sense) and 5 ′ GCG GCT TGA ATG TTT GTC-3 ′ (antisense) [43]; Keap1 5 ′ -CAT CCA CCC TAA GGT CAT GGA-3 ′ (sense) and 5 ′ GAC AGG TTG AAG AAC TCC TCC-3 ′ (antisense) [32]. ...
Diacetylcurcumin manganese complex (DiAc-Cp-Mn) is a diacetylcurcumin (DiAc-Cp) derivative synthesized with Mn (II) to mimic superoxide dismutase (SOD). It exhibited superior reactive oxygen species (ROS) scavenging efficacy, particularly for the superoxide radical. The present study investigated the ROS scavenging activity, neuroprotective effects, and underlying mechanism of action of DiAc-Cp-Mn in a cellular model of Parkinson’s disease. This study utilized rotenone-induced neurotoxicity in SH-SY5Y cells to assess the activities of DiAc-Cp-Mn by measuring cell viability, intracellular ROS, mitochondrial membrane potential (MMP), SOD, and catalase (CAT) activities. The mRNA expression of the nuclear factor erythroid 2 p45-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), inducible nitric oxide synthase (iNOS), and Interleukin 1β (IL-1β), which are oxidative and inflammatory genes, were also evaluated to clarify the molecular mechanism. The results of the in vitro assays showed that DiAc-Cp-Mn exhibited greater scavenging activity against superoxide radicals, hydrogen peroxide, and hydroxyl radicals compared to DiAc-Cp. In cell-based assays, DiAc-Cp-Mn demonstrated greater neuroprotective effects against rotenone-induced neurotoxicity when compared to its parent compound, DiAc-Cp. DiAc-Cp-Mn maintained MMP levels, reduced intracellular ROS levels, and increased the activities of SOD and CAT by activating the Nrf2-Keap1 signaling pathway. In addition, DiAc-Cp-Mn exerted its anti-inflammatory impact by down-regulating the mRNA expression of iNOS and IL-1β that provoked neuro-inflammation. The current study indicates that DiAc-Cp-Mn protects against rotenone-induced neuronal damage by reducing oxidative stress and inflammation.
... Nrf2 regulates the expression of different antioxidant genes, exerting protective effects against oxidative stress (Yamamoto et al., 2018). Activators of Nrf2 generally exert beneficial effects on blood pressure and endothelial dysfunction (Wu et al., 2004;Meephat et al., 2021;Tanase et al., 2022), although Nrf2 downregulation also attenuates hypertension and end-organ damage in type 1 diabetic mice (Zhao et al., 2018). This evidence highlights the need to further study the relevance of antioxidants and Nrf2 activators in the pathogenesis of hypertension and its complications. ...
Inflammatory mechanisms and oxidative stress seem to contribute to the pathogenesis of hypertension. ITH13001 is a melatonin-phenyl-acrylate hybrid that moderately induces the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and has a potent oxidant scavenging effect compared with other derivatives of its family. Here we investigated the effect of ITH13001 on hypertension and the associated cardiovascular alterations. Angiotensin II (AngII)-infused mice were treated with ITH13001 (1 mg/kg per day, i.p.) for 2 weeks. The ITH13001 treatment prevented: 1) the development of hypertension, cardiac hypertrophy, and increased collagen and B-type natriuretic peptide (Bnp) expression in the heart; 2) the reduction of elasticity, incremental distensibility, fenestrae area, intraluminal diameter, and endothelial cell number in mesenteric resistance arteries (MRA); 3) the endothelial dysfunction in aorta and MRA; 4) the plasma and cardiovascular oxidative stress and the reduced aortic nitric oxide (NO) bioavailability; 5) the increased cardiac levels of the cytokines interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 2 (Ccl2), the T cell marker cluster of differentiation 3 (Cd3), the inflammasome NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), the proinflammatory enzymes inducible nitric oxide synthase (iNOS) and COX-2, the toll-like receptor 4 (TLR4) adapter protein myeloid differentiation primary response 88 (MyD88), and the nuclear factor kappa B (NF-κB) subunit p65; 6) the greater aortic expression of the cytokines tumor necrosis factor alpha (Tnf-α), Ccl2 and IL-6, Cd3, iNOS, MyD88, and NLRP3. Although ITH13001 increased nuclear Nrf2 levels and heme oxygenase 1 (HO-1) expression in vascular smooth muscle cells, both cardiac and vascular Nrf2, Ho-1, and NADPH quinone dehydrogenase 1 (Nqo1) levels remained unmodified irrespective of AngII infusion. Summarizing, ITH13001 improved hypertension-associated cardiovascular alterations independently of Nrf2 pathway activation, likely due to its direct antioxidant and anti-inflammatory properties. Therefore, ITH13001 could be a useful therapeutic strategy in patients with resistant hypertension. SIGNIFICANCE STATEMENT: Despite the existing therapeutic arsenal, only half of the patients treated for hypertension have adequately controlled blood pressure; therefore, the search for new compounds to control this pathology and the associated damage to end-target organs (cerebral, cardiac, vascular, renal) is of particular interest. The present study demonstrates that a new melatonin derivative, ITH13001, prevents hypertension development and the associated cardiovascular alterations due to its antioxidant and anti-inflammatory properties, making this compound a potential candidate for treatment of resistant hypertensive patients.
... The XBP1s-HRD1-NRF2 axis exerts functional dichotomy in the cardiorenal system. When the ubiquitination/degradation functionality of the XBP1s-HRD1 axis is inhibited, NRF2 is aberrantly expressed and retained in the nucleus, thus resulting in the dysfunctional expression of RAAS genes, including the upregulation of AGT/ACE genes and the downregulation of ACE2/MasR genes; these effects can aggravate cardiorenal diseases [8,149]. XBP1s can also directly manipulate the expression of some genes that encode components of the RAAS. ...
X-box binding protein 1 (XBP1) is a unique basic-region leucine zipper (bZIP) transcription factor. Over recent years, the powerful biological functions of XBP1 in oxidative stress have been gradually revealed. When the redox balance remains undisturbed, oxidative stress plays a role in physiological adaptations and signal transduction. However, during the aging process, increased cellular senescence and reduced levels of endogenous antioxidants cause an oxidative imbalance in the cardiorenal system. Recent studies from our laboratory and others have indicated that these age-related cardiorenal diseases caused by oxidative stress are guided and controlled by a versatile network composed of diversified XBP1 pathways. In this review, we describe the mechanisms that link XBP1 and oxidative stress in a range of cardiorenal disorders, including mitochondrial instability, inflammation, and alterations in neurohumoral drive. Furthermore, we propose that differing degrees of XBP1 activation may cause beneficial or harmful effects in the cardiorenal system. Gaining a comprehensive understanding of how XBP1 exerts influence on the aging cardiorenal system by regulating oxidative stress will enhance our ability to provide new directions and strategies for cardiovascular and renal safety outcomes.
... Studies involving NRF2 activation yielded controversial results in animal models and patients with diabetes [25][26][27][28][29][30][31][32]. We reported that global deletion of Nrf2 lowered systolic blood pressure (SBP) and decreased angiotensinogen (AGT, the sole precursor of angiotensins) expression in Akita mice, a murine model of T1D [33]. We also showed that Akita Nrf2KO mice overexpressing Nrf2 in RPTCs (Akita Nrf −/− /Nrf2 RPTC transgenic (Tg) mice) resulted in elevated blood glucose level and increased SGLT2 expression in RPTCs versus Akita Nrf2KO mice [17]. ...
... Systolic blood pressure (SBP) was measured via a BP-2000 tail-cuff pressure monitor (Visitech Systems, Apex, NC, USA) at least 2 to 3 times per week [17,33]. Each mouse was accustomed to the procedure for at least 15 to 20 min per day for 5 days before the first SBP measurement at the age of 16 weeks. ...
... Fasting blood glucose (FBG) levels were measured in mice with the Accu-Chek Performa System (Roche Diagnostics, Laval, QC, Canada) after fasting 4 to 6 h or with a glucose colorimetric detection kit (Cayman Chemical, Ann Habor, MI, USA) at the age of 16 weeks, as described previously [17,33]. ...
The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2 diabetes (T2D) db/db mice (db/dbNrf2 knockout (KO)) attenuates DKD progression through the down-regulation of angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), and lipid accumulation in renal proximal tubular cells (RPTCs). Db/dbNrf2 KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with NRF2 KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/dbNrf2 KO mice had lower systolic blood pressure, fasting blood glucose, kidney hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, tubular lipid droplet accumulation, and decreased expression of AGT, SGLT2, CD36, and FABP4 in RPTCs. Male and female mice had similar results. NRF2 KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D.
... The ACE2 levels are regulated by age, gender, or pathological stages [10][11][12][13][14]. For example, ACE2 levels are high in the renal cortical tubules and pancreas islets of young diabetic mice [13][14][15][16][17][18][19][20], whereas ACE2 levels are low in the glomerulus and renal tubules of aged diabetic mice [13,16,18,19,[21][22][23][24]. In human, ACE2 levels are low in respiratory tract epithelial cells under normal physiological condition [9,25]. ...
... Nuclear factor erythroid 2-related factor 2 (Nrf2) Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that belongs to the basic leucine-zipper protein family. ACE2 mRNA and protein levels are decreased in renal proximal tubular cells (RPTCs) of aged type 1 diabetes mice [24]. Treatment of high-concentration glucose increases Nrf2 protein levels in rat RPTCs, whereas ACE2 transcription is reduced in the high-glucose-treated RPTCs [24]. ...
... ACE2 mRNA and protein levels are decreased in renal proximal tubular cells (RPTCs) of aged type 1 diabetes mice [24]. Treatment of high-concentration glucose increases Nrf2 protein levels in rat RPTCs, whereas ACE2 transcription is reduced in the high-glucose-treated RPTCs [24]. The high-glucose-reduced ACE2 protein activity and ACE2 mRNA levels in rat RPTCs are restored by either Nrf2 siRNA knockdown or Nrf2 inhibitor [24]. ...
Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first step of virus infection. ACE2 levels are regulated by transcriptional, post-transcriptional, and post-translational regulation or modification. ACE2 transcription is enhanced by transcription factors including Ikaros, HNFs, GATA6, STAT3 or SIRT1, whereas ACE2 transcription is reduced by the transcription factor Brg1-FoxM1 complex or ERRα. ACE2 levels are also regulated by histone modification or miRNA-induced destabilization. The protein kinase AMPK, CK1α, or MAP4K3 phosphorylates ACE2 protein and induces ACE2 protein levels by decreasing its ubiquitination. The ubiquitination of ACE2 is induced by the E3 ubiquitin ligase MDM2 or UBR4 and decreased by the deubiquitinase UCHL1 or USP50. ACE2 protein levels are also increased by the E3 ligase PIAS4-mediated SUMOylation or the methyltransferase PRMT5-mediated ACE2 methylation, whereas ACE2 protein levels are decreased by AP2-mediated lysosomal degradation. ACE2 is downregulated in several human chronic diseases like diabetes, hypertension, or lung injury. In contrast, SARS-CoV-2 upregulates ACE2 levels, enhancing host cell susceptibility to virus infection. Moreover, soluble ACE2 protein and exosomal ACE2 protein facilitate SARS-CoV-2 infection into host cells. In this review, we summarize the gene regulation and post-translational modification of ACE2 in chronic disease and COVID-19. Understanding the regulation and modification of ACE2 may help to develop prevention or treatment strategies for ACE2-mediated diseases.
... That it has been reported that Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression [99]. ...
The nuclear receptors “NR4As” productive pathway is the so important pathways for activating classic estrogen receptors and are important for regulating the adopted cellular anti-inflammatory growth(mediated by glucocorticoids, Nrf2, Ang2-AT2, and VEGF-A synthesis) which considered as the basic for B-arrestins synthesis which adopt B Adrenergic, and Nrf2 synthesis, that Nrf2 is strong activator to ACE functions for promoting Ang2-AT2 and VEGF-A synthesis for running the adopted anti-inflammatory growth and heme oxygenase. The modulation of oxidative stress will be done by serotonin synthesis(regulated by tryptophan “TGG”) which will promote melatonin synthesis which necessary to activate glucocorticoids productions via NR4A2 pathway followed by B-arrestins and Nrf2 productions for activating Ang2-AT2 and VEGF-A productions. That melatonin synthesis will be associated with GTPase production which promote and activate OPA1 repairs and functions , and responsible for activating glutamine synthesis which stabilize Leucine functions through Nrf2 functions. This study concluded that NR4As productive pathway are the important pathway for improving antioxidation through improving IL6 productivity to IL17 productions, and is important for glucocorticoidsbeta synthesis followed by B-arrestins productions which activate B Adrenergic synthesis that are necessary for activating Nrf2 production that followed by activating ACE for Ang2-AT2 and VEGF-A synthesis for running anti-inflammatory growth, modulating antioxidative stress, activate heme oxygenase, modulating brain function and memories growth , and activating T-cells and B-cell functions. That NR4As exert multilevel regulations of brain function and cardiac functions that protect immune survival from vascular cardiac diseases, and are the primary modulator to pro-inflammation and stimulator for variety of active genes and subunits started by estrogen and GCs-beta productions which followed by activating B-arrestins which activate B Adrenergic synthesis which has the roles of activating Nrf2 productions for adopting antioxidative functions, heme oxygenase, vasoconstriction functions, and anti-inflammatory growth mediated by Ang2-AT2 and VEGF-A synthesis. NR4As pathway has the role of improving cytokines which produced by cDC2s for producing IL6 which improved to IL17 synthesis(upon synthase function and availability of glutamine for supporting Leu synthesis and functions) which necessary for modulating GCs-beta synthesis followed by both B-arrestins synthesis and B Adrenergic then followed by Nrf2 productions,(note ‘N-Acetyl Serotonin activate Nuclear Factor Erythroid 2-Related Factor 2 for Alleviating Oxidative Damage mediated through promoting glutamine synthesis for activating Leu necessary for Nrf2 functions) then followed by activating Ang2-AT2 and VEGF-A necessary for anti-inflammatory growth for T cell functions and B-cell functions(that MZ B-cells which characterized by NR4As expression possess a strong B-cell regulatory functions are the main activator to glucocorticoids, to B-arrestins, and to Nrf2 production for activating Ang2-AT2 and VEGF-A synthesis). Also, this study concluded that β3-adrenergic receptors has important roles for preventing myocardial fibrosis by modulating antioxidative function through activating Nrf2 synthesis that B-adrenergic regulated by B-arrestins via NR4As productive pathway for activating Nrf2 production, that NR4As is a very important pathway for modulating oxidative stress(starred by the stimulation and modulation by serotonin followed by melatonin) for protecting heart, brain and liver functions from oxidative damages and from irregular proliferation activities. Also the β3-adrenergic responsible for lipolysis , and has the role of adoptung both anti-inflammatory growth and antioxidstive processes through activating Nrf2 synthesis followed by activating Ang2-AT2 and VEGF-A productions via NR4As productive pathway(where NRF2’s has imp role is modulating stress response that can now be revised to be included the regulation of the basic functions of stem cells) , that NR4A2 pathway can be concluded to :-
