scholarly journals A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 84
Author(s):  
Bethany L. Goodlett ◽  
Chang Sun Kang ◽  
Eunsoo Yoo ◽  
Shobana Navaneethabalakrishnan ◽  
Dakshnapriya Balasubbramanian ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Immune Cells ◽  
Fractional Excretion ◽  
Vegf Receptor ◽  
Nanoparticle Delivery ◽  
Fractional Excretion Of Sodium ◽  
Induced Hypertension ◽  
Integral Role ◽  
Factor C ◽  
Endothelial Growth Factor

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatics regulate inflammation through clearance of immune cells and excess interstitial fluid. Previously, we demonstrated increasing renal lymphangiogenesis prevents hypertension in mice. We hypothesized that targeted nanoparticle delivery of vascular endothelial growth factor-C (VEGF-C) to the kidney would induce renal lymphangiogenesis, lowering blood pressure in hypertensive mice. A kidney-targeting nanoparticle was loaded with a VEGF receptor-3-specific form of VEGF-C and injected into mice with angiotensin II-induced hypertension or LNAME-induced hypertension every 3 days. Nanoparticle-treated mice exhibited increased renal lymphatic vessel density and width compared to hypertensive mice injected with VEGF-C alone. Nanoparticle-treated mice exhibited decreased systolic blood pressure, decreased pro-inflammatory renal immune cells, and increased urinary fractional excretion of sodium. Our findings demonstrate that pharmacologically expanding renal lymphatics decreases blood pressure and is associated with favorable alterations in renal immune cells and increased sodium excretion.

Abstract P132: A Kidney-Targeted Nanoparticle To Augment Renal Lymphatic Density Decreases Blood Pressure In Mice With L-NAME- And Angiotensin II-Induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Bethany L Goodlett ◽  
Eunsoo Yoo ◽  
Chang Sun Kang ◽  
Dakshnapriya Balasubbramanian ◽  
Sydney Love ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Immune Cells ◽  
Flow Cytometric Analysis ◽  
Lymphatic Vessels ◽  
Fold Increase ◽  
Lower Systolic Blood Pressure ◽  
Induced Hypertension ◽  
Integral Role ◽  
Lymphatic Vasculature

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatic vessels attenuate inflammation by trafficking activated immune cells and excess fluid from the interstitial space to lymph nodes. Previously, our laboratory demonstrated that genetically inducing renal lymphangiogenesis could treat hypertension in three different mouse models. In an effort to translate these findings into a clinical treatment, we hypothesized that a targeted nanoparticle could deliver the pro-lymphangiogenic factor VEGF-C156S to the kidney, induce lymphangiogenesis, and lower blood pressure in hypertensive mice. A micellar nanoparticle was developed with the capacity to deliver protein to the kidney, as demonstrated through delivery trials. This nanoparticle was loaded with VEGF-C156S and injected into mice with LNAME-induced hypertension (LHTN) or angiotensin II-induced hypertension (AIIHTN) via tail vein every 3 days. Compared to hypertensive mice injected with VEGF-C156S only (no nanoparticle) every 3 days, nanoparticle-treated mice exhibited a significantly lower systolic blood pressure (SBP) after 4 injections (LHTN SBP: 160±5 vs. 120±3 mmHg, p<0.001; AIIHTN SBP: 150±8 vs. 126±6 mmHg, p=0.03). Immunolabeled kidney sections from nanoparticle-treated LHTN mice showed a significant increase in podoplanin+ pixels, corresponding to an increase in lymphatic vessel density (p<0.01). A 5-fold increase in renal gene expression of podoplanin in nanoparticle-treated LHTN mice further supported this finding (p=0.01). Flow cytometric analysis of the nanoparticle-treated LHTN mice showed decreased renal CD45+F4/80+CD11c- cells, while AIIHTN mice revealed decreased levels of renal CD45+CD3e+, CD45+CD4+CD8-, and CD45+F4/80+CD11c+ cells (p<0.01, p=0.03, and p<0.001, respectively) when compared to their respective hypertensive groups. These data support our previous findings that expanding the renal lymphatic vasculature can treat existing hypertension by reducing renal immune cells. The results of this study may provide clinicians with a renal lymphatic-targeted therapeutic for treating hypertensive patients.

scholarly journals Deletion of proton-sensing receptor GPR4 associates with lower blood pressure and lower binding of angiotensin II receptor in SFO

2016 ◽  
Vol 311 (6) ◽  
pp. F1260-F1266 ◽  
Author(s):  
Xuming Sun ◽  
Ellen Tommasi ◽  
Doris Molina ◽  
Renu Sah ◽  
K. Bridget Brosnihan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fractional Excretion ◽  
Urine Osmolality ◽  
Brain Regions ◽  
Lower Blood Pressure ◽  
Angiotensin Ii Receptor ◽  
Lower Blood ◽  
Fractional Excretion Of Sodium ◽  
The Impact

Diets rich in grains and meat and low in fruits and vegetables (acid-producing diets) associate with incident hypertension, whereas vegetarian diets associate with lower blood pressure (BP). However, the pathways that sense and mediate the effects of acid-producing diets on BP are unknown. Here, we examined the impact of the deletion of an acid sensor GPR4 on BP. GPR4 is a proton-sensing G protein-coupled receptor and an acid sensor in brain, kidney, and blood vessels. We found that GPR4 mRNA was higher in subfornical organ (SFO) than other brain regions. GPR4 protein was abundant in SFO and present in capillaries throughout the brain. Since SFO partakes in BP regulation through the renin-angiotensin system (RAS), we measured BP in GPR4−/− and GPR4+/+ mice and found that GPR4 deletion associated with lower systolic BP: 87 ± 1 mmHg in GPR4−/− ( n = 35) vs. 99 ± 2 mmHg ( n = 29) in GPR4+/+; P < 0.0001, irrespective of age and sex. Angiotensin II receptors detected by 125I-Sarthran binding were lower in GPR4−/− than GPR4+/+ mice in SFO and in paraventricular nucleus of hypothalamus. Circulating angiotensin peptides were comparable in GPR4−/− and GPR4+/+ mice, as were water intake and excretion, serum and urine osmolality, and fractional excretion of sodium, potassium, or chloride. A mild metabolic acidosis present in GPR4−/− mice did not associate with elevated BP, implying that deficiency of GPR4 may preclude the effect of chronic acidosis on BP. Collectively, these results posit the acid sensor GPR4 as a novel component of central BP control through interactions with the RAS.

scholarly journals Renal effects of oral prostaglandin supplementation after ibuprofen in diabetic subjects: a double-blind, placebo-controlled, multicenter trial.

1995 ◽  
Vol 5 (9) ◽  
pp. 1684-1688
Author(s):  
G L Bakris ◽  
U Starke ◽  
M Heifets ◽  
D Polack ◽  
M Smith ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Insufficiency ◽  
Fractional Excretion ◽  
Multicenter Trial ◽  
Common Side Effect ◽  
Double Blind ◽  
Entire Study ◽  
Fractional Excretion Of Sodium ◽  
Induced Changes

Prostaglandins of the E series (PGE) are known to contribute to the maintenance of renal hemodynamics in subjects with chronic renal insufficiency. Agents that block PGE synthesis, nonsteroidal anti-inflammatory agents (NSAID), are widely used by people with renal insufficiency. This study was undertaken in subjects with renal insufficiency secondary to diabetes to evaluate the acute effects of a PGE1 analog, misoprostol, on NSAID-induced changes in RBF, as calculated by para-aminohippurate clearance, and GFR, as calculated by inulin clearance. Sodium excretion was also assessed. Twenty-five fasting subjects with a mean age of 56 +/- 4 yr received 800 mg of ibuprofen orally. A concomitant dose of either a placebo (PL) or 200 micrograms of misoprostol was also given. This was followed in 1 h by either a placebo or an additional 200-micrograms dose of misoprostol. Measurements for the determination of RBF, GFR, blood pressure, and fractional excretion of sodium were performed every 30 min for the next 5 h. The greatest reduction in both GFR (-25 +/- 7 mL/min per 1.73 m2 PL versus -10 +/- 4 mL/min per 1.73 m2, misoprostol delta GFR; P < 0.05) and RBF (-48 +/- 21 mL/min per 1.73 m2 PL versus -15 +/- 8 mL/min per 1.73 m2, M delta RBF; P < 0.05) occurred approximately 2 h after the NSAID dose. No significant differences were noted in blood pressure, fractional excretion of sodium, or other measured parameters between groups during the entire study. Gastrointestinal upset was the most common side effect observed in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Hacia el esclarecimiento del rol del anión cloruro en la hipertensión arterial: su vínculo con el daño oxidativo en el riñón

2021 ◽  
Vol 89 (2) ◽  
pp. 98-106
Author(s):  
Nicolas M. Kouyoumdzian ◽  
Gabriel Kim ◽  
Gabriel D. Robbesaul ◽  
Paula D. Prince ◽  
Ana M. Puyó ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Systolic Blood Pressure ◽  
Renal Cortex ◽  
Fractional Excretion ◽  
Thiobarbituric Acid ◽  
Standard Diet ◽  
Fractional Excretion Of Sodium ◽  
Male Wistar Rats ◽  
Gpx Activity

Introduction: The role of the chloride anion on the deleterious effects of excessive consumption of salt (NaCl) and whether its effects are independent each other of the presence of sodium remains to date, unknown and unclear. Objective: To demonstrate that both a chloride overload and a sodium overload in the diet produce deleterious effects, by different mechanisms, on systolic blood pressure (SBP), renal function and markers of oxidative stress in the kidney. Materials and Methods: Male Wistar rats were divided into four groups (n = 8 / group) and fed with different diets for three weeks: C: control (standard diet), and diets: NaCl: hypersodic-hyperchloric; Na: hypersodic without chloride and Cl: hyperchloric without sodium. Systolic blood pressure (SBP) and renal function were determined, and the production of thiobarbituric acid reactive species (TBARS) and the activity and expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzymes were evaluated in renal cortex tissue. Results: SBP increased (*) in the two groups fed with chloride. The fractional excretion of sodium and chloride increased (*) in the NaCl and Na groups. increased (*) in the renal cortex with the three diets. No changes were observed in the activity and expression of SOD and CAT. GPx activity increased (*) in the two groups that received chloride; (* p <0.05 vs C). Conclusion: Both sodium and chloride overload are associated with a higher oxidative state characterized by an increase in lipid peroxidation in the renal cortex. However, compared with Na group, only chloride overload is associated with higher GPx activity and hypertension without any changes in urinary chloride excretion, suggesting a higher renal pro-oxidant state in this experimental group.

Fibroblast growth factor 23 is associated with fractional excretion of sodium in patients with chronic kidney disease

2018 ◽  
Vol 34 (12) ◽  
pp. 2051-2057 ◽  
Author(s):  
Hong Xu ◽  
Ali Hashem ◽  
Anna Witasp ◽  
Rik Mencke ◽  
David Goldsmith ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Growth Factor ◽  
Sodium Excretion ◽  
Fibroblast Growth Factor 23 ◽  
Fractional Excretion ◽  
Urinary Sodium Excretion ◽  
Fibroblast Growth ◽  
Fractional Excretion Of Sodium ◽  
Renal Sodium Handling ◽  
Sodium Handling

Abstract Background Recent studies suggest that the phosphaturic hormone fibroblast growth factor 23 (FGF23) is involved in regulation of renal sodium excretion and blood pressure. There is evidence of both direct effects via regulation of the sodium-chloride symporter (NCC) in the distal tubule, and indirect effects through interactions with the renin–angiotensin–aldosterone system. However, clinical data on the association between FGF23 and renal sodium regulation is lacking. Herein, we investigated the associations of FGF23 with renal sodium handling and blood pressure in non-dialysis CKD patients. Methods This was a cross-sectional study encompassing 180 CKD patients Stage 1–5, undergoing renal biopsy. Plasma intact FGF23, 24-h urinary sodium excretion, fractional excretion of sodium (FENa) and blood pressure were measured at baseline. The association between FGF23 and renal sodium handling was explored by multivariate regression analysis. Results The median age was 52.8 years, 60.6% were men and the median estimated glomerular filtration rate (eGFR) was 50.6 mL/min/1.73 m2. In univariate analysis, FGF23 was positively associated with FENa (Spearman’s rho = 0.47; P < 0.001) and systolic blood pressure (rho = 0.17, P < 0.05), but not with plasma sodium, 24-h urinary sodium excretion or mean arterial blood pressure. The association between FGF23 and FENa remained significant after adjustment for potential confounders (multivariable adjusted β coefficient 0.60, P < 0.001). This association was stronger among the 107 individuals with eGFR <60 mL/min/1.73 m2 (β = 0.47, P = 0.04) and in the 73 individuals on any diuretics (β = 0.88, P < 0.001). Adjustment for measured GFR instead of eGFR did not alter the relationship. Conclusions FGF23 is independently associated with increased FENa in non-dialysis CKD patients. These data do not support the notion that FGF23 causes clinically significant sodium retention. Further studies are warranted to explore the mechanism underlying this association.

Effect of inhibition of MAO and COMT on intrarenal dopamine and serotonin and on renal function

2001 ◽  
Vol 280 (1) ◽  
pp. R248-R254 ◽  
Author(s):  
Yongqing Wang ◽  
Theresa J. Berndt ◽  
Jennifer M. Gross ◽  
Michael A. Peterson ◽  
Mathew J. So ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Monoamine Oxidase ◽  
Filtration Rate ◽  
Interstitial Fluid ◽  
Fractional Excretion ◽  
Urine Flow ◽  
Arterial Blood ◽  
Fractional Excretion Of Sodium

The purpose of the present investigation was to study the effects of inhibition of monoamine oxidase (MAO) and/or catechol- O-methyltransferase (COMT), enzymes involved in the degradation of dopamine (DA) and serotonin (5-HT), on intrarenal DA and 5-HT, as reflected in the renal interstitial fluid (RIF) microdialysate and urine, and on renal function. Inhibition of MAO selectively increased RIF 5-HT from 3.16 ± 0.38 to 8.03 ± 1.83 pg/min ( n = 7, P < 0.05), concomitant with decreases in mean arterial blood pressure and glomerular filtration rate (2.09 ± 0.18 to 1.57 ± 0.22 ml/min, n = 7, P < 0.05). Inhibition of COMT significantly increased RIF DA (3.47 ± 0.70 to 8.68 ± 1.96 pg/min, n = 9, P < 0.05), urinary DA (2.00 ± 0.16 to 2.76 ± 0.26 ng/min, n = 9, P < 0.05), and absolute excretion of sodium (6.42 ± 2.00 to 9.82 ± 1.62 μmol/min, n = 10, P < 0.05). Combined inhibition of MAO and COMT significantly increased RIF DA, urinary DA, and urinary 5-HT, which was accompanied with increases in urine flow rate, and absolute (3.03 ± 0.59 to 8.40 ± 1.61 μmol/min, n = 9, P < 0.01) and fractional excretion of sodium. We conclude that inhibition of MAO selectively increases RIF 5-HT. COMT appears to be more important than MAO in the metabolism of intrarenal DA. Physiological increases in intrarenal DA/5-HT induced by inhibition of their degrading enzymes are accompanied with significant alterations of renal function.

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