Kir7.1 knockdown and inhibition alter renal electrolyte handling but not the development of hypertension in Dahl salt-sensitive rats.

High K+ supplementation is correlated with a lower risk of the composite of death, major cardiovascular events, and ameliorated blood pressure, but the exact mechanisms have not been established. Inwardly rectifying K+ (Kir) channels expressed in the basolateral membrane of the distal nephron play an essential role in maintaining electrolyte homeostasis. Mutations in this channel family have been shown to result in strong disturbances in electrolyte homeostasis, among other symptoms. Kir7.1 is a member of the ATP-regulated subfamily of Kir channels. However, its role in renal ion transport and its effect on blood pressure have yet to be established. Our results indicate the localization of Kir7.1 to the basolateral membrane of aldosterone-sensitive distal nephron cells. To examine the physiological implications of Kir7.1, we generated a knockout of Kir7.1 (Kcnj13) in Dahl salt-sensitive (SS) rats and deployed chronic infusion of a specific Kir7.1 inhibitor, ML418, in the wild-type Dahl SS strain. Knockout of Kcnj13 (Kcnj13-/-) resulted in embryonic lethality. Heterozygous Kcnj13+/- rats revealed an increase in K+ excretion on a normal-salt diet but did not exhibit a difference in blood pressure development or plasma electrolytes after 3 wk of a high-salt diet. Wild-type Dahl SS rats exhibited increased renal Kir7.1 expression when dietary K+ was increased. K+ supplementation also demonstrated that Kcnj13+/- rats excreted more K+ on normal salt. The development of hypertension was not different when rats were challenged with high salt for 3 wk, although Kcnj13+/- rats excrete less Na+. Interestingly, chronic infusion of ML418 significantly increased Na+ and Cl- excretion after 14 days of high salt but did not alter salt-induced hypertension development. Here, we found that reduction of Kir7.1 function, either through genetic ablation or pharmacological inhibition, can influence renal electrolyte excretion but not to a sufficient degree to impact the development of SS hypertension.NEW & NOTEWORTHY To investigate the role of the Kir7.1 channel in salt-sensitive hypertension, its function was examined using complementary genetic and pharmacological approaches. The results revealed that although reducing Kir7.1 expression had some impact on maintaining K+ and Na+ balance, it did not lead to a significant change in the development or magnitude of salt-induced hypertension. Hence, it is probable that Kir7.1 works in conjunction with other basolateral K+ channels to fine-tune membrane potential.

Upregulation of Piezo2 in the mesangial, renin, and perivascular mesenchymal cells of the kidney of Dahl salt-sensitive hypertensive rats and its reversal by esaxerenone.

The recent discovery of mechanosensitive ion channels has promoted mechanobiological research in the field of hypertension and nephrology. We previously reported Piezo2 expression in mouse mesangial and juxtaglomerular renin-producing cells, and its modulation by dehydration. This study aimed to investigate how Piezo2 expression is altered in hypertensive nephropathy. The effects of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, were also analyzed. Four-week-old Dahl salt-sensitive rats were randomly assigned to three groups: rats fed a 0.3% NaCl diet (DSN), rats fed a high 8% NaCl diet (DSH), and rats fed a high salt diet supplemented with esaxerenone (DSH + E). After six weeks, DSH rats developed hypertension, albuminuria, glomerular and vascular injuries, and perivascular fibrosis. Esaxerenone effectively decreased blood pressure and ameliorated renal damage. In DSN rats, Piezo2 was expressed in Pdgfrb-positive mesangial and Ren1-positive cells. Piezo2 expression in these cells was enhanced in DSH rats. Moreover, Piezo2-positive cells accumulated in the adventitial layer of intrarenal small arteries and arterioles in DSH rats. These cells were positive for Pdgfrb, Col1a1, and Col3a1, but negative for Acta2 (αSMA), indicating that they were perivascular mesenchymal cells different from myofibroblasts. Piezo2 upregulation was reversed by esaxerenone treatment. Furthermore, Piezo2 inhibition by siRNA in the cultured mesangial cells resulted in upregulation of Tgfb1 expression. Cyclic stretch also upregulated Tgfb1 in both transfections of control siRNA and Piezo2 siRNA. Our findings suggest that Piezo2 may have a contributory role in modulating the pathogenesis of hypertensive nephrosclerosis and have also highlighted the therapeutic effects of esaxerenone on salt-induced hypertensive nephropathy. Mechanochannel Piezo2 is known to be expressed in the mouse mesangial cells and juxtaglomerular renin-producing cells, and this was confirmed in normotensive Dahl-S rats. In salt-induced hypertensive Dahl-S rats, Piezo2 upregulation was observed in the mesangial cells, renin cells, and notably, perivascular mesenchymal cells, suggesting its involvement in kidney fibrosis.

Altered Neuronal Discharge in the Organum Vasculosum of the Lamina Terminalis Contributes to Dahl Salt-Sensitive Hypertension.

BACKGROUND: Salt-sensitive hypertension in humans and experimental models is associated with higher plasma and cerebrospinal fluid sodium chloride (NaCl) concentrations. Changes in extracellular NaCl concentrations are sensed by specialized neurons in the organum vasculosum of the lamina terminalis (OVLT). Stimulation of OVLT neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP), whereas chronic activation produces hypertension. Therefore, the present study tested whether OVLT neuronal activity was elevated and contributed to SNA and ABP in salt-sensitive hypertension. METHODS: Male Dahl salt-sensitive (Dahl S) and Dahl salt-resistant (Dahl R) rats were fed 0.1% or 4.0% NaCl diets for 3 to 4 weeks and used for single-unit recordings of OVLT neurons or simultaneous recording of multiple sympathetic nerves during pharmacological inhibition of the OVLT. RESULTS: Plasma and cerebrospinal fluid Na+ and Cl- concentrations were higher in Dahl S rats fed 4% versus 0.1% or Dahl R rats fed either diet. In vivo single-unit recordings revealed a significantly higher discharge of NaCl-responsive OVLT neurons in Dahl S rats fed 4% versus 0.1% or Dahl R rats. Interestingly, intracarotid infusion of hypertonic NaCl evoked greater increases in OVLT neuronal discharge of Dahl S versus Dahl R rats regardless of NaCl diet. The activity of non-NaCl-responsive OVLT neurons was not different across strain or diets. Finally, inhibition of OVLT neurons by local injection of the gamma-aminobutyric acid agonist muscimol produced a greater decrease in renal SNA, splanchnic SNA, and ABP of Dahl S rats fed 4% versus 0.1% or Dahl R rats. CONCLUSIONS: A high salt diet activates NaCl-responsive OVLT neurons to increase SNA and ABP in salt-sensitive hypertension.

Metabolomics reveals the defense mechanism of histidine supplementation on high-salt exposure-induced hepatic oxidative stress.

AIMS: This study mainly evaluated the protective mechanism of histidine against the hepatic oxidative stress after high-salt exposure (HSE) through combined analysis of non-targeted metabolomics and biological metabolic networks. MATERIALS AND METHODS: Dahl salt-sensitive (SS) rats were fed with normal-salt diet or HSE ± histidine in addition to drinking water for 14 days. Gas chromatography-mass spectrometry was used to analyze the hepatic metabolites. The metabolic profile was analyzed by SIMCA-14.1, the metabolic correlation network was performed using Gephi-0.9.2, and pathway enrichment was analyzed using MetaboAnalyst 5.0 online website. KEY FINDINGS: Results indicated that HSE disturbed the hepatic metabolic profile, generated abnormal liver metabolism and exacerbated oxidative stress. Histidine supplementation significantly reversed the hepatic metabolic profile. Of note, 14 differential metabolic pathways were enriched after histidine supplementation, most of which played an important role in ameliorating redox and nitric oxide (NO) metabolism. Histidine administration decreased the levels of hydroperoxide and malondialdehyde, and increased the activities of antioxidant enzymes (Catalase, Superoxide Dismutase, Glutathione S-transferase and Glutathione reductases). Histidine effectively enhanced the endogenous synthesis of glutathione by increasing the levels of glutamate and cysteine, thereby enhancing the antioxidant capacity of the glutathione system. After histidine administration, lysine, glutamate, and hypotaurine owned a higher metabolic centrality in the correlation network. In addition, histidine could also effectively increase the endogenous synthesis of NO by enhancing the L-arginine/NO pathway. SIGNIFICANCE: This study offers new insights into the metabolic mechanisms underlying the antioxidant protective effect of histidine on the liver.

Shenmai Injection Improves Hypertensive Heart Failure by Inhibiting Myocardial Fibrosis via TGF-ß 1/Smad Pathway Regulation.

OBJECTIVE: To study effects of Shenmai Injection on hypertensive heart failure and its mechanism for inhibiting myocardial fibrosis. METHODS: Salt-sensitive (Dahl/SS) rats were fed with normal diet (0.3% NaCl) and the high-salt diet (8% NaCl) to observe the changes in blood pressure and heart function, as the control group and the model group. Salt-insensitive rats (SS-13BN) were fed with the high-salt diet (8% NaCl) as the negative control group. After modeling, the model rats were randomly divided into heart failure (HF) group, Shenmai Injection (SMI) group and pirfenidone (PFD) group by a random number table, with 6 rats in each group. They were given sterilized water, SMI and pirfenidone, respectively. Blood pressure, cardiac function, fibrosis and related molecular expression were detected by sphygmomanometer, echocardiogram, enzyme linked immunosorbent assay (ELISA), hematoxylin-eosin staining, Masson staining, immunofluorescence and qPCR analysis. RESULTS: After high-salt feeding, compared with the control and negative control group, in the model group the blood pressure increased significantly, the left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) were significantly reduced, and the serum NT-proBNP concentration increased significantly (all P<0.05); furthermore, the arrangement of myocardial cells was disordered, the edema was severe, and the degree of myocardial fibrosis was also significantly increased (P<0.05); the protein and mRNA expressions of collagen type I (Col I) were up-regulated (P<0.05), and the mRNA expressions of transforming growth factor ß 1 (TGF- ß 1), Smad2 and Smad3 were significantly up-regulated (P<0.05). Compared with HF group, after intervention of Shenmai Injection, LVEF and LVFS increased, myocardial morphology was improved, collagen volume fraction decreased significantly (P<0.05), and the mRNA expressions of Col I, TGF- ß 1, Smad2 and Smad3, as well as Col I protein expression, were all significantly down-regulated (all P<0.05). CONCLUSION: Myocardial fibrosis is the main pathological manifestation of hypertensive heart failure, and Shenmai Injection could inhibit myocardial fibrosis and effectively improve heart failure by regulating TGF-ß 1/Smad signaling pathway.

Benincasa hispida extracts positively regulated high salt-induced hypertension in Dahl salt-sensitive rats: Impact on biochemical profile and metabolic patterns.

Salt-induced hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. The objective of this study was to investigate the potential role of Benincasa hispida extracts on high salt-induced hypertension in Dahl-salt sensitive (D-SS) rats and to find out the metabolic and biochemical pattern involved in the reduction of hypertension. Twenty-six Dahl salt-sensitive (D-SS) rats were selected and divided into four groups. The metabolic strategy was applied to test the extracts on salt-sensitive hypertension in kidney. Gas Chromatography-Mass spectrometry (GC-MS) was used to identify the potent biochemical profile in renal medulla and cortex of rat kidneys. The differential metabolites of cortex and medulla, enrichment analysis and pathway analysis were performed using metabolomics data. The GC-MS data revealed that 24 different antihypertensive metabolites was detected in renal cortex, while 16 were detected in renal medulla between different groups. The significantly metabolic pathways namely citrate cycle, glutathione metabolism, glycine, serine, and threonine metabolism, glyoxylate and dicarboxylate metabolism, glycerolipid metabolism, alanine, aspartate and glutamate metabolism in renal cortex and glycerolipid metabolism, pentose phosphate pathway, citrate cycle, glycolysis, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis in renal medulla were involved in the process of Hypertension. The results suggest that the extract mainly alter the metabolic pathways of amino acid in Dahl salt-sensitive rats and its antioxidant potential reduced the hypertension patterns of Salt-sensitive rat. The antihypertensive components malic acid, aspartic acid, and glycine of extract can be used as therapeutic drugs to protect kidneys from salt-induced hypertension. PRACTICAL APPLICATIONS: Hypertension is a multifactorial disease and one of the risk factors for heart and kidney failure. Benincasa hispida is a widely used vegetable in China, which belongs to the Cucurbitaceae family. Benincasa hispida (wax gourd) has been used in traditional Chinese medicine for the treatment of inflammation and hypertension. The Benincasa hispida contains many compounds such as amino acids, carbohydrates, volatile compounds, vitamins, and minerals. The amino acid present in the pulp of Benincasa hispida are ornithine, threonine, aspartate, glutamate, serine, glycine, proline, alanine, valine, cysteine, isoleucine, tyrosine, leucine, lysine, phenylalanine, histidine, arginine, and γ-aminobutyric acid. Our results showed that Benincasa hispida is one of the potent natural antioxidants and can maintain normal blood pressure in Dahl salt-sensitive rats (D-SS). In conclusion, the current results provide good theoretical basis for the development and research using Benincasa hispida as an effective natural antioxidant for hypertension.

Momordica charantia Extract Confers Protection Against Hypertension in Dahl Salt-Sensitive Rats.

Hypertension is one of the main factors of cardiovascular disease worldwide and is strongly related to the overall mortality. High salt intake is a major risk factors for hypertension. Identifying functional foods that can help prevent mechanistic abnormalities mediating salt-induced hypertension is an issue of considerable nutraceutical and scientific interest. Dietary Momordica charantia may be an alternative approach to avoid salt-induced hypertension. Dahl salt-sensitive (DSS) rats were used to determine whether Momordica charantia water extracts (ME) exerts anti-hypertensive effects in the present study. ME gavage could significantly prevented the increase of blood pressure, blood urea nitrogen, creatinine, and urine protein-to-creatinine ratio of DSS rats. Metabolomics analysis indicated that high-salt diet induced abnormal amino acid metabolism was related to nitric oxide (NO) deficiency, but ME gavage could upregulate the activities of nitric oxide synthase, aspartate aminotransferase, argininosuccinate lyase, argininosuccinate synthase and restore endogenous synthesis of arginine and NO. Meanwhile, renal function was improved after ME gavage. Citrulline, as one of the important component in ME, could attenuate salt-induced hypertension by increasing endogenous synthesis of arginine and NO. Antioxidants in ME, such as phenolic compound, may avoid high-salt induced oxidative stress in DSS rats, which may be another mechanism by which ME prevented blood pressure increase. Thus, the present study indicated that feeding Momordica charantia could avoid high-salt-induced hypertension in DSS rats.

Supplementation of amino acids and organic acids prevents the increase in blood pressure induced by high salt in Dahl salt-sensitive rats.

A high-salt (HS) diet leads to metabolic disorders in Dahl salt-sensitive (SS) rats, and promotes the development of hypertension. According to the changes in the metabolites of SS rats, a set of combined dietary supplements containing amino acids and organic acids (AO) were designed. The purpose of the present study was to evaluate the effect of AO supplementation on the blood pressure of SS rats after the HS diet and clarify the mechanism of AO by metabolomics and biochemical analyses. The results showed that AO supplementation avoided the elevation of blood pressure induced by the HS diet in SS rats, increased the renal antioxidant enzyme activities (catalase, superoxide dismutase, glutathione reductase, and glutathione S-transferase), reduced the H2O2 and MDA levels, and restored the normal antioxidant status of the serum and kidneys. AO also reversed the decrease in the nitric oxide (NO) levels and NO synthase activity induced by the HS feed, which involved the L-arginine/NO pathway. Metabolomics analysis showed that AO administration increased the levels of amino acids such as cysteine, glycine, hypotaurine, and lysine in the renal medulla and the levels of leucine, isoleucine, and serine in the renal cortex. Of note, lysine, hypotaurine and glycine had higher metabolic centrality in the metabolic correlation network of the renal medulla after AO administration. In conclusion, AO intervention could prevent HS diet-induced hypertension in SS rats by restoring the metabolic homeostasis of the kidneys. Hence, AO has the potential to become a functional food additive to improve salt-sensitive hypertension.

The effects of choreito on a model of nocturnal polyuria using Dahl salt-sensitive rats.

OBJECTIVES: This study aimed to determine whether Dahl salt-sensitive rats fed a high-salt diet would show features of nocturia due to nocturnal polyuria and to examine the efficacy of choreito (CRT) on nocturnal polyuria. METHODS: Dahl salt-sensitive rats were divided into three groups. Group A was fed a 4% salt diet, group B a 2% salt diet, and group C a normal 0.3% salt diet. In groups α and ß, other rats were further divided into two groups: The rats in group α were fed a 2% salt plus 3% CRT diet, and those in group ß, were fed a 2% salt diet. Each rat was placed in an individual metabolic cage for 24 hours every week for 6 weeks. Water intake, urine production, voiding frequency, and voided volume per micturition were recorded. RESULTS: The systolic blood pressure increased in the group fed a 4% salt diet compared to groups fed with a 2% and 0.3% salt diet. The urinary volume was higher in the groups fed with 4% and 2% salt than in the group fed with 0.3% salt. Further, water intake in the group fed a 2% salt plus 3% CRT diet was significantly lower than that in the group fed with a 2% salt diet. CONCLUSIONS: Dahl salt-sensitive rats fed a 2% salt diet were candidates for a model of nocturnal polyuria. Using this model, we suggest that CRT reduces water intake in the active phase and contributes to water restriction in the treatment of nocturnal polyuria.

ß-Aminoisobutyric acid supplementation attenuated salt-sensitive hypertension in Dahl salt-sensitive rats through prevention of insufficient fumarase.

The human Dietary Approaches to Stop Hypertension-Sodium Trial has shown that ß-aminoisobutyric acid (BAIBA) may prevent the development of salt-sensitive hypertension (SSHT). However, the specific antihypertensive mechanism remains unclear in the renal tissues of salt-sensitive (SS) rats. In this study, BAIBA (100 mg/kg/day) significantly attenuated SSHT via increased nitric oxide (NO) content in the renal medulla, and it induced a significant increase in NO synthesis substrates (L-arginine and malic acid) in the renal medulla. BAIBA enhanced the activity levels of total NO synthase (NOS), inducible NOS, and constitutive NOS. BAIBA resulted in increased fumarase activity and decreased fumaric acid content in the renal medulla. The high-salt diet (HSD) decreased fumarase expression in the renal cortex, and BAIBA increased fumarase expression in the renal medulla and renal cortex. Furthermore, in the renal medulla, BAIBA increased the levels of ATP, ADP, AMP, and ADP/ATP ratio, thus further activating AMPK phosphorylation. BAIBA prevented the decrease in renal medullary antioxidative defenses induced by the HSD. In conclusion, BAIBA's antihypertensive effect was underlined by the phosphorylation of AMPK, the prevention of fumarase's activity reduction caused by the HSD, and the enhancement of NO content, which in concert attenuated SSHT in SS rats.

Periconceptional 1,3-butanediol supplementation suppresses the superimposed preeclampsia-like phenotype in the Dahl salt-sensitive rat.

Preeclampsia is a hypertensive pregnancy disorder with no treatment beyond management of symptoms and delivery of the fetus and placenta. Chronic hypertension increases the risk of developing superimposed preeclampsia. Previous reports showed that 1,3-butanediol attenuates hypertension in rodents; however, the therapeutic potential of 1,3-butanediol for the prevention of preeclampsia has not been investigated. This study tested the hypothesis that attenuating hypertension before pregnancy and through the placentation period via 1,3-butanediol prevents the onset of preeclampsia in female Dahl salt-sensitive (SS/Jr) rats. Female Dahl SS/Jr rats were divided into two groups: 1,3-butanediol treated (20% via drinking water) and control (ad libitum water). Both groups were maintained on low-salt rodent chow (Teklad 7034, 0.3% NaCl; n = 8/group). Animals were treated with 1,3-butanediol for 7 wk (baseline), mated, and treated through day 12 of pregnancy. 1,3-Butanediol treatment increased plasma ß-hydroxybutyrate (metabolite of 1,3-butanediol) that negatively correlated with maternal body weight in late pregnancy. Mean arterial pressure was lower in the treated group at baseline, early, and mid pregnancy, but no difference was observed in late pregnancy after treatment ended. Uterine artery resistance index (UARI) was reduced in the treated dams. No adverse fetal effects were observed, and there were no differences in pup weight or length. Placentas from treated dams had decreased vascular endothelial growth factor levels as well as decreased placental basal zone thickness and increased labyrinth zone thickness. These findings support the therapeutic role of physiological ketosis via 1,3-butanediol as a potential therapeutic approach for managing chronic hypertension, thereby preventing and mitigating adverse pregnancy outcomes associated with preeclampsia.NEW & NOTEWORTHY A ketogenic diet or increased ß-hydroxybutyrate levels can reduce hypertension, but the potential of 1,3-butanediol, a ß-hydroxybutyrate precursor, for treatment of preeclampsia is unknown. We hypothesized that attenuating hypertension before and during pregnancy via 1,3-butanediol prevents preeclampsia in Dahl Salt-sensitive rats. 1,3-Butanediol significantly lowered blood pressure and improved uterine artery resistance with no observable adverse fetal effects. Physiological ketosis via 1,3-butanediol may be a potential therapeutic approach for managing hypertension and mitigating adverse pregnancy outcomes.

Effects of almonds on ameliorating salt-induced hypertension in dahl salt-sensitive rats.

BACKGROUND: Excessive dietary salt intake is related to an increased risk of hypertension. Dietary functional foods probably could help to improve salt-induced hypertension. In this study, Dahl salt-sensitive (DSS) rats were used to investigate their metabolic differences from those of salt-resistant SS.13BN rats and determine whether dietary protein-rich almonds could ameliorate salt-induced elevation of blood pressure in DSS rats. RESULTS: After high-salt intake, the systolic blood pressure and mean arterial pressure of the DSS rats increased dramatically. Metabolomics analysis indicated abnormal amino acid metabolism in their kidneys. Their renal nitric oxide (NO) content and nitric oxide synthase activity decreased significantly after high-salt diet. Oxidative stress also occurred in DSS rats. After the DSS rats received almond supplementation, the levels of various amino acids in their kidney increased, and renal arginine and NO contents were upregulated. Their renal hydrogen peroxide and malonaldehyde levels decreased, whereas renal catalase, superoxide dismutase and glutathione peroxidase activities and glutathione levels increased. CONCLUSION: The renal abnormal amino acid metabolism of DSS rats contributed to the impaired NO production in response to high-salt intake. Together with salt-induced oxidative stress, high-salt diet intake ultimately led to an increase in the blood pressure of DSS rats. Protein-rich almond supplementation might prevent the development of salt-induced hypertension by restoring arginine and NO regeneration and alleviating salt-induced oxidative stress. © 2021 Society of Chemical Industry.

ANKRD36 Is Involved in Hypertension by Altering Expression of ENaC Genes.

[Figure: see text].

Endogenous Taurine Downregulation Is Required for Renal Injury in Salt-Sensitive Hypertensive Rats via CBS/H2S Inhibition.

Although taurine is known to exert an antihypertensive effect, it is unclear whether it is involved in the mechanism for hypertension-related target organ injury. To reveal the role of endogenous taurine in renal injury formation during salt-sensitive hypertension and clarify its mechanisms, both salt-sensitive Dahl rats and salt-resistant SS-13BN rats were fed a high-salt diet (8% NaCl) and given 2% taurine for 6 weeks. Rat systolic blood pressure (SBP) was measured by the tail-cuff method and artery catheterization. Kidney ultrastructure was observed under an electron microscope. Taurine content and mRNA and protein levels of taurine synthases, cysteine dioxygenase type 1 (CDO1) and cysteine sulfinic acid decarboxylase (CSAD), were decreased in Dahl rats fed a high-salt diet. However, taurine supplementation and the resulting increase in renal taurine content reduced the increased SBP and improved renal function and structural damage in high-salt diet-fed Dahl rats. In contrast, taurine did not affect SS-13BN SBP and renal function and structure. Taurine intervention increased the renal H2S content and enhanced cystathionine-ß-synthase (CBS) expression and activity in Dahl rats fed a high-salt diet. Taurine reduced the renin, angiotensin II, and aldosterone contents and the levels of oxidative stress indices in Dahl rat renal tissues but increased antioxidant capacity, antioxidant enzyme activity, and protein expression. However, taurine failed to achieve this effect in the renal tissue of SS-13BN rats fed a high-salt diet. Pretreatment with the CBS inhibitor HA or renal CBS knockdown inhibited H2S generation and subsequently blocked the effect of taurine on renin, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) levels in high-salt-stimulated Dahl renal slices. In conclusion, the downregulation of endogenous taurine production resulted in a decrease in the renal CBS/H2S pathway. This decrease subsequently promoted renin-angiotensin-aldosterone system (RAAS) activation and oxidative stress in the kidney, ultimately contributing to renal injury in salt-sensitive Dahl rats.

QiShenYiQi ameliorates salt-induced hypertensive nephropathy by balancing ADRA1D and SIK1 expression in Dahl salt-sensitive rats.

BACKGROUND: Hypertension is a leading risk factor for developing kidney disease. Current single-target antihypertensive drugs are not effective for hypertensive nephropathy, in part due to its less understood mechanism of pathogenesis. We recently showed that QiShenYiQi (QSYQ), a component-based cardiovascular Chinese medicine, is also effective for ischemic stroke. Given the important role of the brain-heart-kidney axis in blood pressure control, we hypothesized that QSYQ may contribute to blood pressure regulation and kidney protection in Dahl salt-sensitive hypertensive rats. METHODS: The therapeutic effects of QSYQ on blood pressure and kidney injury in Dahl salt-sensitive rats fed with high salt for 9 weeks were evaluated by tail-cuff blood pressure monitoring, renal histopathological examination and biochemical indicators in urine and serum. RNA-seq was conducted to identify QSYQ regulated genes in hypertensive kidney, and RT-qPCR, immunohistochemistry, and Western blotting analysis were performed to verify the transcriptomics results and validate the purposed mechanisms. RESULTS: QSYQ treatment significantly decreased blood pressure in Dahl salt-sensitive hypertensive rats, alleviated renal tissue damage, reduced renal interstitial fibrosis and collagen deposition, and improved renal physiological function. RNA-seq and subsequent bioinformatic analysis showed that the expression of ADRA1D and SIK1 genes were among the most prominently altered by QSYQ in salt-sensitive hypertensive rat kidney. RT-qPCR, immunohistochemistry and Western blotting results confirmed that the mRNA and protein expression levels of alpha-1D adrenergic receptor (ADRA1D) in the kidney tissue of the QSYQ-treated rats were markedly down-regulated, while the mRNA and protein levels of salt inducible kinase 1 (SIK1) were significantly increased. CONCLUSION: QSYQ not only lowered blood pressure, but also alleviated renal damage via reducing the expression of ADRA1D and increasing the expression of SIK1 in the kidney of Dahl salt-sensitive hypertensive rats.

Eucommia ulmoides (Tochu) and its extract geniposidic acid reduced blood pressure and improved renal hemodynamics.

INTRODUCTION: Eucommia ulmoides leaves are used as Tochu tea, which has a blood pressure lowering effect of unknown mechanism. PURPOSE AND METHODS: The effects of Tochu tea and its component, geniposidic acid, on blood pressure and renal hemodynamics were investigated in Dahl salt-sensitive (DS) rats received 1% saline solution from 4 weeks of age. At 9 weeks of age, 1% saline alone (DSHS), Tochu tea extract added 1% saline (DSHS+T), or geniposidic acid added 1% saline (DSHS+G) was administered for another 4 weeks. DS rats fed with tap water were used as controls (DSLS). At 13 weeks, the blood pressure, the renal plasma flow (RPF) and the renal NADPH oxidase, endothelial nitric oxide synthase (eNOS) were examined. RESULTS: Blood pressure in DSHS rats was significantly increased in comparison to DSLS (144 vs. 196 mmHg, p < 0.01), and was significantly reduced in DSHS+T (158 mmHg) and DSHS+G (162 mmHg) rats. RPF in DSHS+T rats was significantly higher than in DSHS rats (p < 0.05). The expression of NADPH oxidase in DSHS rats was enhanced in comparison to DSLS rats; however, it was suppressed in DSHS+T and DSHS+G rats, and the NO production by eNOS was increased; thus, RPF was improved. The urinary Na excretion in DSHS rats was higher than that in DSLS rats; however it was further increased in DSHS+T rats without changes in the tubular Na transporters. CONCLUSION: Tochu tea and geniposidic acid suppressed NADPH oxidase, increased eNOS, and improved blood pressure and renal hemodynamics.

L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4.

Amino acid metabolism plays an important role in controlling blood pressure by regulating the production of NO and ROS. The present study examined amino acid levels in the serum of Dahl SS rats and SS.13BN rats fed a low or high salt diet. We observed that 8 of 27 amino acids responded to a high salt diet in SS rats. Thus, we hypothesized that a defect in amino acids may contribute to the development of salt-induced hypertension. L-phenylalanine was used to treat SS rats with a low or high salt diet. The results demonstrated that L-phenylalanine supplementation significantly enhanced the serum nitrite levels and attenuated the high salt-induced hypertension in SS rats. Low levels of BH4 and nitrite and the impaired vascular response to acetylcholine were rescued by L-phenylalanine supplementation. Moreover, increased GTP cyclohydrolase (GCH1) mRNA, levels of BH4 and nitrite, and reduced superoxide production were observed in the kidneys of hypertensive SS rats with L-phenylalanine. The antihypertensive effects of L-phenylalanine might be mediated by enhancing BH4 biosynthesis and decreasing superoxide production from NO synthase, thereby protecting vascular and kidney function with reduced ROS and elevated NO levels. The present study demonstrated that L-phenylalanine supplementation restored vascular function, suggesting L-phenylalanine represented a potential target to attenuate high salt-sensitive hypertension through GCH1-BH4.

Nicotinamide for the treatment of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.

Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding Kir5.1) knockout in the Dahl salt-sensitive rat (SSKcnj16-/-), which caused electrolyte/pH dysregulation and high-salt diet-induced mortality. Since Kir channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SSKcnj16-/- rats would exhibit neurological phenotypes, including increased susceptibility to seizures. SSKcnj16-/- rats exhibited increased light sensitivity (fMRI) and reproducible sound-induced tonic-clonic audiogenic seizures confirmed by electroencephalography. Repeated seizure induction altered behavior, exacerbated hypokalemia, and led to approximately 38% mortality in male SSKcnj16-/- rats. Dietary potassium supplementation did not prevent audiogenic seizures but mitigated hypokalemia and prevented mortality induced by repeated seizures. These results reveal a distinct, nonredundant role for Kir5.1 channels in the brain, introduce a rat model of audiogenic seizures, and suggest that yet-to-be identified mutations in Kcnj16 may cause or contribute to seizure disorders.

Traditional Chinese medicine protects against hypertensive kidney injury in Dahl salt-sensitive rats by targeting transforming growth factor-ß signaling pathway.

This study investigated the therapeutic efficacy of Bu-Shen-Jiang-Ya decoction (BSJYD) on hypertensive renal damage to determine whether it regulates the expression of transforming growth factor-ß (TGF-ß)/SMADs signaling pathways, thereby relieving renal fibrosis in Dahl salt-sensitive (SS) rats. Dahl SS rats on a high-sodium diet were prospectively treated with BSJYD (n = 12) or valsartan (n = 12) for 8 weeks. The blood pressure (BP) of these rats was measured and their kidneys were subjected to biochemical analysis, including serum creatinine (Scr) and blood urea nitrogen (BUN); hematoxylin and eosin staining; Masson trichrome staining; real-time polymerase chain reaction; and western blot analysis. The primary outcome was that BSJYD significantly reduced BP, debased BUN, and Scr and ameliorated renal pathological changes. As underlying therapeutic mechanisms, BSJYD reduces TGFß1 and Smad2/3 expression and suppresses renal fibrosis, as suggested by the decreased expression of connective tissue growth factor(CTGF). These data suggest that BSJYD acts as an optimal therapeutic agent for hypertensive renal damage by inhibiting the TGF-ß/SMADs signaling pathway.