A Novel Cell Volume Sensor for Real-Time Analysis of Ca2+-Activated K+ Channel.

Potassium channels play a vital role in cell volume regulation. A cell volume sensor was constructed by integrating regulatory volume decrease (RVD) with quartz-crystal microbalance (QCM) for studying potassium channels and their expression. The sensor successfully monitored the K+ channel's activities during RVD by sensitive and noninvasive means. It showed that Ca2+ activated the K+ channel (KCa) and enhanced the RVD level. The inhibition of blockers on K+ channels exhibited an obvious difference in RVD level between normal and cancerous nasopharyngeal cells, suggesting that the KCa channel contributes a dominant role to the RVD function and provides an approach to identify the activation of various K+ channels.

Renal Farnesoid X Receptor improves high fructose-induced salt-sensitive hypertension in mice by inhibiting DNM3 to promote nitro oxide production.

OBJECTIVE: Farnesoid X Receptor (FXR) is highly expressed in renal tubules, activation of which attenuates renal injury by suppressing inflammation and fibrosis. However, whether renal FXR contributes to the regulation of blood pressure (BP) is poorly understood. This study aimed to investigate the anti-hypertensive effect of renal FXR on high-fructose-induced salt-sensitive hypertension and underlying mechanism. METHODS: Hypertension was induced in male C57BL/6 mice by 20% fructose in drinking water with 4% sodium chloride in diet (HFS) for 8 weeks. The effects of FXR on NO production were estimated in vitro and in vivo . RESULTS: Compared with control, HFS intake elevated BP, enhanced renal injury and reduced renal NO levels as well as FXR expression in the kidney of mice. In the mouse renal collecting duct cells mIMCD-K2, FXR agonists promoted NO production by enhancing the expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), whereas this effect was diminished by fxr knockdown. We further found that Dynamin 3 (DNM3), a binding protein with nNOS in the renal medulla, was inhibited by FXR and its deficiency elevated NO production in mIMCD-K2 cells. In HFS-fed mice, renal fxr overexpression significantly attenuated hypertension and renal fibrosis, regulated the expression of DNM3/nNOS/iNOS, and increased renal NO levels. CONCLUSION: Our results demonstrated that renal FXR prevents HFS-induced hypertension by inhibiting DNM3 to promote NO production. These findings provide insights into the role and potential mechanism of renal FXR for the treatment of hypertension.

Moderation of gut microbiota and bile acid metabolism by chlorogenic acid improves high-fructose-induced salt-sensitive hypertension in mice.

Chlorogenic acid (CGA) is a natural compound with many important pharmacological effects including anti-hypertension. This study aimed to investigate the anti-hypertensive effect of CGA on high-fructose-induced salt-sensitive hypertension and the underlying mechanism. Hypertension was induced in male C57BL/6 mice by 20% fructose in drinking water plus 4% sodium chloride in the diet (HFS) for 8 weeks. CGA (50, 100 or 200 mg kg-1 d-1) was orally administered to HFS-treated mice. The blood pressure of mice was recorded via the tail cuff method. The structure of gut microbiota and profiles of bile acids (BAs) in the serum were determined. Here, we found that HFS-elevated systolic blood pressure was greatly attenuated by CGA. The microbiota analysis showed that CGA restructured the HFS-treated gut microbiota, and markedly enriched Klebsiella. Oral administration of a Klebsiella isolate, Klebsiella oxytoca, also exhibited an anti-hypertensive effect in HFS-fed mice. Furthermore, we found that CGA and CGA-enriched K. oxytoca enhanced the expression of colonic Farnesoid X Receptor (FXR), modulated BA metabolism and enriched some BAs including deoxycholic acid (DCA) in the serum of HFS-fed mice. Treatment with DCA improved phenylephrine-induced vasoconstriction in arterioles of mice and attenuated hypertension in HFS-fed mice, suggesting that DCA serves as a link between gut microbiota and blood pressure. Our results clearly demonstrate that CGA attenuates HFS-induced hypertension in mice by modulating gut microbiota and BA metabolism. These findings provide insights into the potential mechanism of CGA for the treatment of hypertension.

Enterococcus faecalis contributes to hypertension and renal injury in Sprague-Dawley rats by disturbing lipid metabolism.

OBJECTIVE: Increasing studies have demonstrated that gut microbiota play vital roles in the development of hypertension. However, the underlying mechanism is not fully understood. METHODS: The relative abundance of Enterococcus faecalis was determined in the faecal samples of angiotensin II or deoxycorticosterone acetate/salt-induced hypertensive rats. Then, E. faecalis culture was administered orally to rats for 6 weeks. Blood pressure (BP) was measured, renal injury was estimated and a serum metabolomic analysis was performed. RESULTS: Compared with control, E. faecalis was markedly enriched in the faecal samples of hypertensive rats. The rats receiving live E. faecalis but not dead bacteria exhibited higher BP and enhanced renal injury. The serum metabolomic data showed that the E. faecalis treatment resulted in 35 variable metabolites including 16 (46%) lipid/lipid-like molecules, suggesting significant disturbance of lipid metabolism. Furthermore, the mRNA levels of 18 lipid metabolic enzymes in the renal medulla and cortex presented distinct and dynamic changes in response to 3 or 6-week E. faecalis treatment. Consistently, the protein levels of lysophospholipases A1 (LYPLA1) and phospholipase A2 group 4 A (PLA2G4) were enhanced only by live E. faecalis, which thus may have decreased the nitric oxide production in the renal medulla and elevated BP. CONCLUSION: Our results suggest that E. faecalis in the gut contributes to hypertension and renal injury in rats by disturbing the lipid metabolism. The information provided here could shed new light on the pathologic mechanisms and potential intervention targets for the treatment of gut dysbiosis-induced hypertension.

Sodium butyrate ameliorates deoxycorticosterone acetate/salt-induced hypertension and renal damage by inhibiting the MR/SGK1 pathway.

Our recent work demonstrates that infusion of sodium butyrate (NaBu) into the renal medulla blunts angiotensin II-induced hypertension and improves renal injury. The present study aimed to test whether oral administration of NaBu attenuates salt-sensitive hypertension in deoxycorticosterone acetate (DOCA)/salt-treated rats. Uninephrectomized male Sprague-Dawley (SD) rats were treated with DOCA pellets (150 mg/rat) plus 1% NaCl drinking water for 2 weeks. Animals received oral administration of NaBu (1 g/kg) or vehicle once per day. Our results showed that NaBu administration significantly attenuated DOCA/salt-increased mean arterial pressure from 156 ± 4 mmHg to 136 ± 1 mmHg. DOCA/salt treatment markedly enhanced renal damage as indicated by an increased ratio of kidney weight/body weight, elevated urinary albumin, extensive fibrosis, and inflammation, whereas kidneys from NaBu-treated rats exhibited a significant reduction in these renal damage responses. Compared to the DOCA/salt group, the DOCA/salt-NaBu group had ~30% less salt water intake and decreased Na+ and Cl- excretion in urine but no alteration in 24-h urine excretion. Mechanistically, NaBu inhibited the protein levels of several sodium transporters stimulated by DOCA/salt in vivo, such as ßENaC, γENaC, NCC, and NKCC-2. Further examination showed that NaBu downregulated the expression of mineralocorticoid receptor (MR) and serum and glucocorticoid-dependent protein kinase 1 (SGK1) in DOCA/salt-treated rats or aldosterone-treated human renal tubular duct epithelial cells. These results provide evidence that NaBu may attenuate DOCA/salt-induced hypertension and renal damage by inhibiting the MR/SGK1 pathway.

Correction: ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway.

ELABELA (ELA), a 32-residue hormone peptide abundantly expressed in adult kidneys, has been identified as a novel endogenous ligand for APJ/Apelin receptor. The aim of this study was to investigate the role of ELA in deoxycorticosterone acetate (DOCA)/salt-induced hypertension and further explore the underlying mechanism. In DOCA/salt-treated rats, the mRNA level of ELA greatly decreased in the renal medulla. Next, overexpression of ELA in the kidney was found to attenuate DOCA/salt-induced hypertension and renal injury, including lower blood pressure, reversed glomerular morphological damage, decreased blood urea nitrogen (BUN), and blocked the accumulation of fibrotic markers. Mechanistically, ELA overexpression inhibited renal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subsequent reactive oxygen species (ROS) production, thus resulted in the blockade of formation and activation of Nod-like receptor protein 3 (NLRP3) inflammasome. The inhibitory effects of ELA on Aldosterone-stimulated NADPH oxidase/ROS/NLRP3 inflammasome pathway were confirmed in the human renal tubular cells. Furthermore, our in vivo and in vitro results showed that the deficiency of the apelin receptor APJ did not influence the antihypertensive effect and blockage to NADPH oxidase/ROS/NLRP3 pathway of ELA. Moreover, in heterozygous ELA knockout mice (ELA+/-), the ELA deficiency remarkably accelerated the onset of DOCA/salt-induced hypertension. Our data demonstrate that ELA prevents DOCA/salt-induced hypertension by inhibiting NADPH oxidase/ROS/NLRP3 pathway in the kidney, which is APJ independent. Pharmacological targeting of ELA may serve as a novel therapeutic strategy for the treatment of hypertensive kidney disease.

Gut dysbiosis contributes to high fructose-induced salt-sensitive hypertension in Sprague-Dawley rats.

OBJECTIVES: Although it is known that high fructose intake causes salt-sensitive hypertension, the underlying mechanism remains unclear. The aim of this study was to determine whether chronic intake of high fructose coupled with salt (HFS) might alter the structure of the gut microbiota, which contributes to elevated blood pressure. METHODS: For 8 wk, Sprague-Dawley rats were given 20% fructose in drinking water and 4% sodium chloride in their diet to induce hypertension. A non-absorbable antibiotic vancomycin was used to modify gut microbiota. The 16 S rRNA sequencing for fecal samples was assessed and blood pressure was recorded. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to examine the renin-angiotensin system in serum, urine, and the kidney. RESULTS: Compared with the control group, HFS feeding resulted in gut dysbiosis by altering the diversity and richness of gut microbiota and decreased the ratio of Firmicutes to Bacteroidetes. Vancomycin reshaped dramatically the HFS-induced dysbiosis. And vancomycin (van) attenuated HFS-increased blood pressure (HFS: 121.3 ± 2.8 mm Hg; HFS-van: 111.1 ± 1.7 mm Hg) and heart rate (HFS: 360.5 ± 9.0 bpm; HFS-van: 318.7 ± 5.6 bpm) as well as the content of angiotensinogen, renin, and angiotensin II in the urine and the angiotensinogen mRNA level in renal cortical tissues. However, HFS-increased triacylglycerol, renin, and angiotensin II in serum were not decreased by vancomycin. CONCLUSION: The present results demonstrated that gut dysbiosis develops after chronic fructose plus salt intake and contributes to the increase of blood pressure and the activation of the intrarenal renin-angiotensin system. Therefore, targeting gut microbiota provides a helpful therapy method to improve HFS-induced hypertension.