Effects of vasoactive substances on biomechanics of small resistance arteries of male and female Dahl salt-sensitive rats.

Changes in vascular biomechanics leading to increase in arterial stiffness play a pivotal role in circulatory dysfunction. Our objectives were to examine sex-specific pharmacological changes related to the biomechanics and any structural modifications in small resistance arteries of Dahl salt-sensitive male and female rats. The composite Young modulus (CYM) was determined using pressure myograph recordings, and immunohistochemistry was used for the evaluation of any structural changes in the third-order mesenteric arteries (n = 6). Animals on high-salt diet developed hypertension with significant elevation in central and peripheral blood pressures and pulse wave velocity compared to those on regular diet. There were no significant differences observed in the CYM between any of the groups (i.e., males and females) in vehicle-treated time-control studies. The presence of verapamil (0.3 µM) significantly reduced CYM in hypertensive males without changes within females compared to vehicle. This effect was abolished by phenylephrine (0.3 µM). BaCl2 (100 µM), ouabain (100 µM), and L-NAME (0.3 µM) combined significantly increased CYM in vessels from in normotensive males and females but not in hypertensive males compared to vehicle. The increase in CYM was abolished in the presence of phenylephrine. Sodium nitroprusside (0.3 µM), in the presence of phenylephrine, significantly reduced CYM in male normotensive versus hypertensive, with no differences within females. Significant differences were observed in immunohistochemical assessment of biomechanical markers of arterial stiffness between males and females. Our findings suggest sex possibly due to pressure differences to be responsible for adaptive changes in biomechanics, and varied pharmacological responses in hypertensive state.

Canagliflozin attenuates kidney injury, gut-derived toxins, and gut microbiota imbalance in high-salt diet-fed Dahl salt-sensitive rats.

PURPOSE: To investigate the effects of canagliflozin (20 mg/kg) on Dahl salt-sensitive (DSS) rat gut microbiota and salt-sensitive hypertension-induced kidney injury and further explore its possible mechanism. METHODS: Rats were fed a high-salt diet to induce hypertension and kidney injury, and physical and physiological indicators were measured afterwards. This study employed 16S rRNA sequencing technology and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolic profiling combined with advanced differential and association analyses to investigate the correlation between the microbiome and the metabolome in male DSS rats. RESULTS: A high-salt diet disrupted the balance of the intestinal flora and increased toxic metabolites (methyhistidines, creatinine, homocitrulline, and indoxyl sulfate), resulting in severe kidney damage. Canagliflozin contributed to reconstructing the intestinal flora of DSS rats by significantly increasing the abundance of Corynebacterium spp., Bifidobacterium spp., Facklamia spp., Lactobacillus spp., Ruminococcus spp., Blautia spp., Coprococcus spp., and Allobaculum spp. Moreover, the reconstruction of the intestinal microbiota led to significant changes in host amino acid metabolite concentrations. The concentration of uremic toxins, such as methyhistidines, creatinine, and homocitrulline, in the serum of rats was decreased by canagliflozin, which resulted in oxidative stress and renal injury alleviation. CONCLUSION: Canagliflozin may change the production of metabolites and reduce the level of uremic toxins in the blood circulation by reconstructing the intestinal flora of DSS rats fed a high-salt diet, ultimately alleviating oxidative stress and renal injury.

T-cells regulate albuminuria but not hypertension, renal histology, or the medullary transcriptome in the Dahl SSCD247+/+ rat.

In the current study, we took advantage of the loss of protection from hypertension in SSCD247-/- rats to characterize the pathological effects of renal T-cells in isolation from the confounding effects of elevated renal perfusion pressure. Male SSCD247-/- and SSCD247+/+ littermates were fed 4.0% NaCl (high salt) diet to induce hypertension. Blood pressure was assessed continuously throughout the time course with radiotelemetry. Urine albumin and protein excretion were assessed on the final day of high salt. Renal injury and medullary transcriptome were assessed after completion of the high salt protocol. In contrast to previous studies, mean arterial pressure was not significantly different between SSCD247-/- and SSCD247+/+ rats. Despite this lack of pressure difference, urinary albumin was significantly lower in SSCD247-/- rats than their wild-type littermates. In the outer medulla, substantially more transcriptomic changes were found to correlate with endpoint blood pressure than with the absence of presence of renal T-cells. We also demonstrated that renal histological damage was driven by elevated renal perfusion pressure rather than the presence of renal T-cells. In conclusion, using the loss of protection from hypertension in SSCD247-/- rats, we demonstrated that renal perfusion pressure has more profound pathological effects on the kidney than renal T-cells. However, renal T-cells, independently of blood pressure, modulate the progression of albuminuria.NEW & NOTEWORTHY In vivo studies in a T-cell-deficient rat model of salt-sensitive hypertension (SSCD247-/- rats) were used to evaluate the role of T-cells on the development of hypertension and renal damage. Detailed physiological and transcriptomic analysis demonstrated no difference in blood pressure between rats with (SSCD247+/+) or without (SSCD247-/-) T-cells. Despite this, albuminuria was significantly lower in SSCD247-/- rats than SSCD247+/+ rats.

Transcriptomic changes in glomeruli in response to a high salt challenge in the Dahl SS rat.

Salt sensitivity impacts a significant portion of the population and is an important contributor to the development of chronic kidney disease. One of the significant early predictors of salt-induced damage is albuminuria, which reflects the deterioration of the renal filtration barrier: the glomerulus. Despite significant research efforts, there is still a gap in knowledge regarding the molecular mechanisms and signaling networks contributing to instigating and/or perpetuating salt-induced glomerular injury. To address this gap, we used 8-wk-old male Dahl salt-sensitive rats fed a normal-salt diet (0.4% NaCl) or challenged with a high-salt diet (4% NaCl) for 3 wk. At the end of the protocol, a pure fraction of renal glomeruli obtained by differential sieving was used for next-generation RNA sequencing and comprehensive semi-automatic transcriptomic data analyses, which revealed 149 differentially expressed genes (107 and 42 genes were downregulated and upregulated, respectively). Furthermore, a combination of predictive gene correlation networks and computational bioinformatic analyses revealed pathways impacted by a high salt dietary challenge, including renal metabolism, mitochondrial function, apoptotic signaling and fibrosis, cell cycle, inflammatory and immune responses, circadian clock, cytoskeletal organization, G protein-coupled receptor signaling, and calcium transport. In conclusion, we report here novel transcriptomic interactions and corresponding predicted pathways affecting glomeruli under salt-induced stress.NEW & NOTEWORTHY Our study demonstrated novel pathways affecting glomeruli under stress induced by dietary salt. Predictive gene correlation networks and bioinformatic semi-automatic analysis revealed changes in the pathways relevant to mitochondrial function, inflammatory, apoptotic/fibrotic processes, and cell calcium transport.

High-salt diet induces dyslipidemia through the SREBP2/PCSK9 pathway in dahl salt-sensitive rats.

A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.

Dapansutrile Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in HFpEF Rats.

BACKGROUND: Numerous studies have demonstrated that NLRP3 inflammasomes are key players in the progression of atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF). This study aimed to analyse the effect of pharmacological inhibition of NLRP3 inflammasomes using dapansutrile (DAPA), an oral NLRP3-specific inhibitor. METHODS: Dahl salt-sensitive rats were fed a high-salt diet (HSD, 8% NaCl) to induce HFpEF. Either DAPA (200 mg/kg/day) or saline was administered daily via gavage for 4 weeks. Electrophysiological studies were performed to assess the AF inducibility. Confocal fluorescence microscopy and western blot analysis were used to study calcium handling. RESULTS: The DAPA-treated HFpEF rats were less prone to AF induction by programmed electrical stimulation. Atrial fibrosis and inflammation were attenuated in DAPA-treated HFpEF hearts. Dapansutrile treatment showed an increase in the Ca2+ transient sarcoplasmic reticulum-Ca2+ load, and protein expression of SERCA2; NCX1 and phosphorylation of PLB at Thr17 were decreased following DAPA treatment. The increased frequency of spontaneous Ca2+ spark in the HFpEF rats was related to the hyperphosphorylation of RyR2 at Ser2814, which was blunted in DAPA treatment. Dapansutrile treatment also decreased the phosphorylation of CaMKII expression in the HFpEF rats. Mechanistically, DAPA exerts an anti-arrhythmic effect, mainly by inhibiting activation of the NLRP3 inflammasome. CONCLUSION: These data provide evidence that the beneficial cardiac effects of DAPA are associated with reduced atrial inflammation and improved CaMKII-dependent Ca2+-handling abnormalities via blunting activation of the NLRP3 inflammasome, and DAPA may be beneficial in a rat model of HFpEF-induced AF.

Hypoxia-inducible factor-prolyl hydroxylase inhibitor Roxadustat (FG-4592) reduces renal fibrosis in Dahl salt-sensitive rats.

OBJECTIVE: Although hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anemia, their effects on cardiac and renal dysfunction remain unknown. We previously reported on Dahl salt-sensitive rats, in a rat model of salt-sensitive hypertension, that exhibited anemia and impaired expression of duodenal iron transporters after the development of hypertensive cardiac and renal dysfunction. Therefore, we investigated the effects of Roxadustat (FG-4592), an HIF-PH inhibitor, on anemia, iron regulation, and cardiac and renal dysfunction in Dahl salt-sensitive rats. METHODS: Six-week-old male Dahl salt-sensitive rats were fed a normal or high-salt diet for 8 weeks. A further subset of Dahl salt-sensitive rats, that were fed a high-salt diet, was administered Roxadustat for 8 weeks. RESULTS: Dahl salt-sensitive rats fed a high-salt diet developed hypertension, cardiac and renal dysfunction, and anemia after 8 weeks of feeding. Roxadustat increased hemoglobin and serum erythropoietin levels in Dahl salt-sensitive rats fed a high-salt diet. With regard to the iron-regulating system, Roxadustat lowered hepatic hepcidin gene expression and increased the gene expression of duodenal iron transporters, such as cytochrome b and divalent metal transporter 1 , in Dahl salt-sensitive rats fed a high-salt diet. Roxadustat did not affect the development of hypertension and cardiac hypertrophy in Dahl salt-sensitive rats with a high-salt diet; however, Roxadustat treatment attenuated renal fibrosis in these rats. CONCLUSIONS: Roxadustat ameliorated anemia with affecting the gene expression of the iron-regulating system, and did not affect cardiac hypertrophy but attenuated renal fibrosis in Dahl salt-sensitive rats fed a high-salt diet.

Perivascular Adipose Tissue Remodels Only after Elevation of Blood Pressure in the Dahl SS Rat Fed a High-Fat Diet.

INTRODUCTION: Tunica media extracellular matrix (ECM) remodeling is well understood to occur in response to elevated blood pressure, unlike the remodeling of other tunicas. We hypothesize that perivascular adipose tissue (PVAT) is responsive to hypertension and remodels as a protective measure. METHODS: The adventitia and PVAT of the thoracic aorta were used in measuring ECM genes from 5 pairs of Dahl SS male rats on 8 or 24 weeks of feeding from weaning on a control (10% Kcal fat) or high-fat (HF; 60%) diet. A PCR array of ECM genes was performed with cDNA from adventitia and PVAT after 8 and 24 weeks. A gene regulatory network of the differentially expressed genes (DEGs) (HF 2-fold > con) was created using Cytoscape. RESULTS: After 8 weeks, 29 adventitia but 0 PVAT DEGs were found. By contrast, at 24 weeks, PVAT possessed 47 DEGs while adventitia had 3. Top DEGs at 8 weeks in adventitia were thrombospondin 1 and collagen 8a1. At 24 weeks, thrombospondin 1 was also a top DEG in PVAT. The transcription factor Adarb1 was identified as a regulator of DEGs in 8-week adventitia and 24-week PVAT. CONCLUSION: These data support that PVAT responds biologically once blood pressure is elevated.

Single cell transcriptome analyses reveal the roles of B cells in fructose-induced hypertension.

Rationale: While the immune system plays a crucial role in the development of hypertension, the specific contributions of distinct immune cell populations remain incompletely understood. The emergence of single-cell RNA-sequencing (scRNA-seq) technology enables us to analyze the transcriptomes of individual immune cells and to assess the significance of each immune cell type in hypertension development. Objective: We aimed to investigate the hypothesis that B cells play a crucial role in the development of fructose-induced hypertension. Methods and Results: Eight-week-old Dahl salt-sensitive (SS) male rats were divided into two groups and given either tap water (TW) or a 20% fructose solution (HFS) for 4 weeks. Systolic blood pressure was measured using the tail-cuff method. ScRNA-seq analysis was performed on lamina propria cells (LPs) and peripheral blood mononuclear cells (PBMCs) obtained from SS rats subjected to either TW or HFS. The HFS treatment induced hypertension in the SS rats. The analysis revealed 27 clusters in LPs and 28 clusters in PBMCs, allowing for the identification and characterization of various immune cell types within each cluster. Specifically, B cells and follicular helper T (Tfh) cells were prominent in LPs, while B cells and M1 macrophages dominated PBMCs in the HFS group. Moreover, the HFS treatment triggered an increase in the number of B cells in both LPs and PBMCs, accompanied by activation of the interferon pathway. Conclusions: The significant involvement of B cells in intestinal and PBMC responses indicates their pivotal contribution to the development of hypertension. This finding suggests that targeting B cells could be a potential strategy to mitigate high blood pressure in fructose-induced hypertension. Moreover, the simultaneous increase in follicular B cells and Tfh cells in LPs, along with the upregulation of interferon pathway genes in B cells, underscores a potential autoimmune factor contributing to the pathogenesis of fructose-induced hypertension in the intestine.

ß-Arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage.

Angiotensin receptor blockers (ARBs) are the first-line treatment for hypertension; they act by inhibiting signaling through the angiotensin 1 receptor (AT1R). Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the ß-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication. Here, we explored the effects of TRV and associated ß-arrestin signaling in podocytes, essential cells of the kidney filter. We used human podocyte cell lines to determine ß-arrestin's involvement in calcium signaling and cytoskeletal reorganization and Dahl SS rats to investigate the chronic effects of TRV administration on glomerular health. Our experiments indicate that the TRV-activated ß-arrestin pathway promotes the rapid elevation of intracellular Ca2+ in a dose-dependent manner. Interestingly, the amplitude of ß-arrestin-mediated Ca2+ influx was significantly higher than the response to similar Ang II concentrations. Single-channel analyses show rapid activation of transient receptor potential canonical (TRPC) channels following acute TRV application. Furthermore, the pharmacological blockade of TRPC6 significantly attenuated the ß-arrestin-mediated Ca2+ influx. Additionally, prolonged activation of the ß-arrestin pathway in podocytes resulted in pathological actin cytoskeleton rearrangements, higher apoptotic cell markers, and augmented glomerular damage. TRV-activated ß-arrestin signaling in podocytes may promote TRPC6 channel-mediated Ca2+ influx, foot process effacement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment requires further investigation to assess the balance of the benefits versus possible deleterious effects and off-target damage.

Effects of Exercise Training on Mitochondrial Fatty Acid ß-Oxidation in the Kidneys of Dahl Salt-Sensitive Rats.

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16-20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of ß-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of ß-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid ß-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney.

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats.

In proteinuric renal diseases, the serine protease (SP) plasmin activates the epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-salt (HS) diet provoked hypertension and proteinuria in Dahl salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by camostat mesilate (CM), an SP inhibitor. However, the effects of CM on plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited hypertension, massive proteinuria, increased urinary plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented plasmin(ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic cytokine expression. Our findings highlight the detrimental role of urinary plasmin in the pathogenesis of salt-sensitive hypertension and glomerular injury. Targeting plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions.

Effect of SGLT2 inhibition on salt-induced hypertension in female Dahl SS rats.

Sodium-glucose co-transporters (SGLTs) in the kidneys play a pivotal role in glucose reabsorption. Several clinical and population-based studies revealed the beneficial effects of SGLT2 inhibition on hypertension. Recent work from our lab provided significant new insight into the role of SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension, Dahl salt-sensitive (SS) rats. Dapagliflozin (Dapa) blunted the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in the Renin-Angiotensin-Aldosterone System. However, our initial study used male SS rats only, and the effect of SGLT2 inhibitors on hypertension in females has not been studied. Therefore, the goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function in female Dahl SS rats. The result showed that administration of Dapa for 3 weeks prevented the progression of salt-induced hypertension in female rats, similar to its effects in male SS rats. Diuresis and glucose excretion were significantly increased in Dapa-treated rats. SGLT2 inhibition also significantly attenuated kidney but not heart fibrosis. Despite significant effects on blood pressure, Dapa treatment caused minor changes to electrolyte balance and no effects on kidney and heart weights were observed. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex.

Pericyte detachment and renal congestion involve interstitial injury and fibrosis in Dahl salt-sensitive rats and humans with heart failure.

Congestive heart failure produces fluid volume overload, central and renal venous pressure elevation, and consequently renal congestion, which results in worsening renal function. Pericyte detachment and pericyte-myofibroblast transition (PMT) were linked to renal interstitial fibrosis. Dahl salt-sensitive hypertensive (DahlS) rats are a non-surgical renal congestion model. The relation, however, between renal interstitial damage, pericyte morphology, and PMT in the renal congestion of DahlS rats has not been reported. DahlS rats (8-week-old) were fed normal salt (NS, 0.4% NaCl) or high salt (HS, 4% NaCl), and the left kidney was decapsulated to reduce renal interstitial hydrostatic pressure (RIHP) at 9 weeks old. One week after capsulotomy, both kidneys were analyzed by molecular and histological techniques. Renal pericyte structure was assessed in the body donors with/without venous stasis. Markers of tubulointerstitial damage, interstitial fibrosis, and PMT were upregulated in the right non-decapsulated kidney of DahlS rats fed HS. Renal tubular injury and fibrosis were detected in the HS diet groups in histological analysis. Pericyte detachment was observed in the right non-decapsulated kidney of DahlS rats fed HS by low vacuum-scanning electron microscopy. Decapsulation in DahlS rats fed HS attenuated these findings. Also, renal pericytes detached from the vascular wall in patients with heart failure. These results suggest that pericyte detachment and PMT induced by increased RIHP are responsible for tubulointerstitial injury and fibrosis in DahlS rats and humans with renal congestion. Renal venous congestion and subsequent physiological changes could be therapeutic targets for renal damage in cardiorenal syndrome.

Dimethyl Fumarate Ameliorated Cardiorenal Anemia Syndrome and Improved Overall Survival in Dahl/Salt-Sensitive Rats.

Cardiovascular disease, chronic kidney disease, and anemia are known to adversely affect each other. Inflammation is commonly involved in these diseases. Cardiorenal anemia syndrome (CRAS) is the name given to this mutually harmful condition. Dimethyl fumarate (DMF) is a Food and Drug Administration-approved antioxidant and anti-inflammatory agent. The purpose of this study was to investigate the effects of DMF on Dahl/salt-sensitive (DS) rats as a CRAS model. Six-week-old DS rats were divided into three groups: the control group, the high-salt (HS) group, and the HS+DMF group. The HS and HS+DMF groups were fed a high-salt diet (8% NaCl) from 6 weeks of age. In the HS+DMF group, DMF (90 mg/kg per day) was orally administered from 6 to 15 weeks of age. Systolic blood pressure was measured every 2 weeks. The heart and renal injuries were assessed with histopathological analysis. The heart and renal expression of mRNAs was assessed by reverse-transcription polymerase chain reaction. DMF significantly improved overall survival, which was shortened by HS in DS rats. Systolic blood pressure increased in the HS group compared with the control group, and DMF tended to suppress this change. DMF ameliorated the cardiac and renal abnormalities confirmed in the HS group by histopathological analysis. Furthermore, the changes in mRNA expressions associated with disease exacerbation in the HS group were suppressed by DMF. DMF also improved anemia. This study suggests that DMF improves overall survival in DS rats through organ-protective effects and is effective against cardiorenal anemia syndrome. SIGNIFICANCE STATEMENT: Dimethyl fumarate was found to improve overall survival in Dahl/salt-sensitive rats, associated with its ability to ameliorate anemia and induce cardioprotective and renoprotective effects through anti-inflammatory and antifibrotic effects.

Canagliflozin and irbesartan ameliorate renal fibrosis via the TGF-ß1/Smad signaling pathway in Dahl salt-sensitive rats.

OBJECTIVES: This study assessed the antifibrotic effects of canagliflozin, with or without irbesartan, on renal injury in Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. METHODS: After the preconditioning stage, Dahl SS rats (n = 47) were divided into five experimental groups as follows: low-salt (LS, n = 7), HS (n = 10), HS with canagliflozin (n = 10), HS with irbesartan (n = 10), and HS with canagliflozin and irbesartan (n = 10). RESULTS: The HS diet increased systolic blood pressure (SBP), renal fibrosis, fibrotic protein expression, and transforming growth factor-ß1 (TGF-ß1)/Smad2/3 pathway protein expression compared with the findings in the LS group. Irbesartan reduced SBP and slowed the loss of renal function. Canagliflozin significantly reduced body weight and renal fibrosis and suppressed the TGF-ß1/Smad2/3 pathway. The combined therapy exerted better renoprotective effects on all outcome parameters. CONCLUSIONS: These results indicate that canagliflozin and irbesartan exert different effects on renal injury in SS hypertensive rats, and the combined regimen could have stronger effects than either monotherapy.

Autoregulatory mission impossible: when afferent arterioles lose contractility.

The myogenic response of afferent arterioles is a key autoregulatory mechanism that protects the glomeruli from barotrauma. Afferent arteriolar smooth muscle cells contract to increased intraluminal pressure through mechanosensitive cation channels and interactions between integrin and extracellular matrix that trigger calcium-dependent actomyosin contraction. The study by Feng et al. provides evidence supporting the concept that increased matrix metalloproteinase 9 in kidney microvessels of Dahl salt-sensitive rats interferes with integrin-matrix binding and promotes phenotypic transformation of afferent arterioles, causing loss of myogenic constriction and hypertensive nephropathy.

Canagliflozin Ameliorates Ventricular Remodeling through Apelin/Angiotensin-Converting Enzyme 2 Signaling in Heart Failure with Preserved Ejection Fraction Rats.

INTRODUCTION: The aim of this study was to investigate the effect of canagliflozin (CANA) on ventricular remodeling in patients with preserved ejection fraction (HFpEF) heart failure and to further investigate its possible molecular mechanisms. METHODS: A high-salt diet was used to induce the formation of HFpEF model in salt-sensitive rats. The rats were fed with CANA and irbesartan, respectively. The mice were divided into control group, model group, CANA group, irbesartan group, and combined drug group. After 12 weeks of feeding, the rats were evaluated by measuring the relevant indexes and echocardiography for cardiac function. Histological analysis was performed using Masson trichrome staining and immunohistochemical staining. RT-qPCR and Western blot were used to quantify the relevant genes and proteins. RESULTS: In this study, CANA exhibited diuresis, decreased blood pressure, weight loss, and increased food and water intake. Following a high-salt diet, Dahl salt-sensitive rats developed hypertension followed by left ventricular diastolic dysfunction, myocardial fibrosis, and left ventricular remodeling. Myocardial hypertrophy and fibrosis were reduced, and left ventricular diastolic function and ventricular remodeling improved after CANA treatment. The combination of CANA and irbesartan was superior to monotherapy in reducing blood pressure and improving cardiac insufficiency and left ventricular diastolic dysfunction in rats. CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling by upregulating apelin, activating angiotensin-converting enzyme 2 (ACE2), and increasing ACE2/Ang (1-7)/MASR axis levels. CONCLUSION: CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling in HFpEF rats through upregulation of apelin/ACE2 signaling.