scholarly journals Synergic Renoprotective Effects Of Combined ASC Therapy With RAAS Blockade In Experimental Advanced CKD

2021 ◽  
Author(s):  
Marina PC Maires ◽  
Krislley R Pereira ◽  
Everidiene KVB Silva ◽  
Victor HR Souza ◽  
Flavio Teles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Conservative Management ◽  
Experimental Models ◽  
Ckd Progression ◽  
Renal Inflammation ◽  
Raas Blockade ◽  
Beneficial Effects ◽  
Renal Ablation

ABSTRACTGlobal prevalence of chronic kidney disease (CKD) has increased considerably in the recent decades. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to renal inflammation and fibrosis contribute to its evolution. The treatments currently employed to control CKD progression are limited and mainly based on the pharmacological inhibition of RAAS, associated with diuretics and immunosuppressive drugs. However, this conservative management promotes only partial deceleration of CKD evolution, and does not completely avoid the progression of the disease and the loss of renal function, which motivates the medical and scientific community to investigate new therapeutic approaches to detain renal inflammation / fibrosis and CKD progression. Recent studies have shown the application of mesenchymal stem cells (mSC) to exert beneficial effects on the renal tissue of animals submitted to experimental models of CKD. In this context, the aim of the present study was to evaluate the effects of subcapsular application of adipose tissue-derived mSC (ASC) in rats submitted to the 5/6 renal ablation model, 15 days after the establishment of CKD, when the nephropathy was already severe. We also verify whether ASC associated to Losartan, would promote greater renoprotection when compared to the respective monotherapies. Animals were followed until 30 days of CKD, when body weight, systolic blood pressure, biochemical, histological, immunohistochemical and gene expression analysis were performed. The combination of ASC and Losartan was more effective than Losartan monotherapy in reducing systolic blood pressure and glomerulosclerosis, and also promoted the complete normalization of proteinuria and albuminuria, a significant reduction in renal interstitial macrophage infiltration and downregulation of renal IL-6 gene expression. The beneficial effects of ACS are possibly due to the immunomodulatory and anti-inflammatory role of factors secreted by these cells, modulating the local immune response. Although studies are still required, our results demonstrated that a subcapsular inoculation of ASC, associated with the administration of Losartan, exerted additional renoprotective effect in rats submitted to a severe model of established CKD, when compared to Losartan monotherapy, thus suggesting ASC may be a potential adjuvant to RAAS-blockade therapy currently employed in the conservative management of CKD.

The effects of dietary nitrate on blood pressure and endothelial function: a review of human intervention studies

2013 ◽  
Vol 26 (2) ◽  
pp. 210-222 ◽  
Author(s):  
Ditte A. Hobbs ◽  
Trevor W. George ◽  
Julie A. Lovegrove
Keyword(s):  
Blood Pressure ◽  
Endothelial Function ◽  
Systolic Blood Pressure ◽  
Intervention Studies ◽  
Blood Pressure Reduction ◽  
Oral Bacteria ◽  
Human Intervention ◽  
Dietary Nitrate ◽  
Beneficial Effects ◽  
Healthy Humans

Evidence has accumulated in recent years that suggests that nitrate from the diet, particularly vegetables, is capable of producing bioactive NO in the vasculature, following bioconversion to nitrite by oral bacteria. The aim of the present review was to consider the current body of evidence for potential beneficial effects of dietary nitrate on blood pressure and endothelial function, with emphasis on evidence from acute and chronic human intervention studies. The studies to date suggest that dietary nitrate acutely lowers blood pressure in healthy humans. An inverse relationship was seen between dose of nitrate consumed and corresponding systolic blood pressure reduction, with doses of nitrate as low as 3 mmol of nitrate reducing systolic blood pressure by 3 mmHg. Moreover, the current studies provide some promising evidence on the beneficial effects of dietary nitrate on endothelial function.In vitrostudies suggest a number of potential mechanisms by which dietary nitrate and its sequential reduction to NO may reduce blood pressure and improve endothelial function, such as: acting as a substrate for endothelial NO synthase; increasing vasodilation; inhibiting mitochondrial reactive oxygen species production and platelet aggregation. In conclusion, the evidence for beneficial effects of dietary nitrate on blood pressure and endothelial function is promising. Further long-term randomised controlled human intervention studies assessing the potential effects of dietary nitrate on blood pressure and endothelial function are needed, particularly in individuals with hypertension and at risk of CVD.

scholarly journals Antihypertensive effect of biotin in stroke-prone spontaneously hypertensive rats

2008 ◽  
Vol 99 (4) ◽  
pp. 756-763 ◽  
Author(s):  
Mari Watanabe-Kamiyama ◽  
Shin Kamiyama ◽  
Kimiko Horiuchi ◽  
Kousaku Ohinata ◽  
Hitoshi Shirakawa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Spontaneously Hypertensive Rat ◽  
Biotin Deficiency ◽  
Hypotensive Action ◽  
Spontaneously Hypertensive ◽  
Beneficial Effects ◽  
Synthase Inhibitor

Biotin is a member of the vitamin B-complex family. Biotin deficiency has been associated with hyperglycaemia and insulin resistance in animals and humans. In the present study, we investigated the pharmacological effects of biotin on hypertension in the stroke-prone spontaneously hypertensive rat (SHRSP) strain. We observed that long-term administration of biotin decreased systolic blood pressure in the SHRSP strain; also, a single dose of biotin immediately decreased systolic blood pressure in this strain. Pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole [4,3-α]quinoxalin-1-one abolished the hypotensive action of biotin in the SHRSP strain, while pretreatment with the NO synthase inhibitor NG-nitro-l-arginine methyl ester had no effect on the action of biotin. Biotin reduced coronary arterial thickening and the incidence of stroke in the SHRSP strain. These results suggest that the pharmacological dose of biotin decreased the blood pressure of the SHRSP via an NO-independent direct activation of soluble guanylate cyclase. Our findings reveal the beneficial effects of biotin on hypertension and the incidence of stroke.

scholarly journals Iron Deficiency Modifies Gene Expression Variation Induced by Augmented Hypoxia Sensing

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1765-1765
Author(s):  
Victor R. Gordeuk ◽  
Xu Zhang ◽  
Wei Zhang ◽  
Shwu-Fan Ma ◽  
Galina Miasniakova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Pressure ◽  
Pulmonary Hypertension ◽  
Iron Deficiency ◽  
Systolic Blood Pressure ◽  
Iron Status ◽  
Induction Effect ◽  
Systolic Pulmonary Artery Pressure ◽  
Altered Regulation ◽  
Upregulated Genes

Abstract Abstract 1765 Hypoxia may cause pulmonary and brain edema, pulmonary hypertension, aberrant metabolism and early mortality. To better understand pathological processes associated with hypoxia, we examined gene expression in Chuvash polycythemia blood mononuclear cells. Chuvash polycythemia is a congenital disorder of up-regulated hypoxic response at normoxia wherein VHLR200W homozygosity leads to elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, thromboses, pulmonary hypertension, lower systemic blood pressure (SBP) and increased mortality. VHLR200W homozygotes are often treated by phlebotomy resulting in iron deficiency, allowing us to evaluate an interaction of augmented hypoxia sensing with iron deficiency. Expression profiling of 8 VHLR200W homozygotes and 17 VHL wildtype individuals, matched for normal iron status as reflected in serum ferritin concentration, revealed altered regulation of 3069 genes at false discovery rate <0.05, with 847 up-regulated and 2222 down-regulated in VHLR200W homozygotes. Genes induced by homozygous VHLR200W were enriched in immune response pathways; those repressed in RNA transcription and protein synthesis pathways. Forty-two genes showed a >1.5-fold change in expression level, mostly (74%) an increase. Seven showed a >2-fold increase: CA1 (carbonic anhydrase), SELENBP1 (selenium binding protein 1), IL1B (interleukin 1 beta), SLC4A1 (solute carrier family 4 member 1), HBB (hemoglobin beta), and AHSP (alpha hemoglobin stabilizing protein). Additional studies including 16 VHLR200W homozygotes with low ferritin indicated that iron deficiency enhanced the induction effect of VHLR200W for 51 of the 847 upregulated genes and suppressed the induction effect for 108 of the upregulated genes. Genes further upregulated by iron deficiency included CA1, CSDA (cold shock domain protein A), BCL2L1 (BCL-2 like 1), BPGM (2,3-bisphosphoglycerate mutase), DCAF12 (DDB1 and CUL4 associated factor 12), FECH (ferrochelatase), SELENBP1 and SLC4A1. Genes for which iron deficiency suppressed the induction included inflammatory and immune pathway genes such as CASP5, CXCL16, IFI30, IFI35, IRF5, LILRB1, NOD2, RELT, TCIRG1 and TNFAIP2. A number of the genes with altered regulation in VHLR200W homozygotes might modify risk of thrombosis (upregulated: F3, SERPINE1, SERPINB2, SERPING1, PLAUR, THBD; down regulated: SERBP1), elevated systolic pulmonary artery pressure (upregulated: HTR1B, THBS1; downregulated: S1PR1, STIM2), or benign hemangioma (downregulated: CCM2). However, expression of these genes tended not to be influenced by iron status. VEGF was induced in VHLR200W homozygotes and surprisingly this induction was suppressed by iron deficiency. Expression relationships suggested a broad effect of VHLR200W in reducing systolic blood pressure through inducing VEGF. We demonstrate that many genes have commensurate changes of their expression by both iron deficiency and VHLR200W associated normoxic up-regulation of HIFs, as expected. However, there are genes that are regulated asynchronously. Further research is needed to define the molecular bases of separate regulation of genes by HIFs and iron status and to define relative risks and benefits of therapeutic phlebotomy for polycythemia. The resulting elucidation of the genomic pathways affecting predisposition to thromboses, pulmonary hypertension, lower systolic blood pressure and the interaction of augmented hypoxia sensing with iron deficiency should have broad implications leading to a better understanding of the pathophysiology of many diseases and the development of targeted therapies. Disclosures: No relevant conflicts of interest to declare.

Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats

1996 ◽  
Vol 271 (1) ◽  
pp. H88-H93 ◽  
Author(s):  
J. S. Li ◽  
L. Knafo ◽  
A. Turgeon ◽  
R. Garcia ◽  
E. L. Schiffrin
Keyword(s):  
Gene Expression ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Blood Vessels ◽  
Renovascular Hypertension ◽  
Vascular Structure ◽  
Hypertensive Rats ◽  
Blood Pressure Elevation ◽  
Vascular Hypertrophy ◽  
Endothelin 1

To investigate the potential pathogenic role of endothelin in blood pressure elevation and vascular hypertrophy in renovascular hypertensive rats, which present twofold elevations in endothelin-1 mRNA abundance in blood vessels, the response of blood pressure and vascular structure to chronic treatment with the endothelin receptor antagonist bosentan was evaluated. One-kidney, one clip (1K,1C) and two kidney, one clip (2K,1C) Goldblatt hypertensive rats were treated for 2 wk with bosentan (100 mg.kg-1.day-1) in their chow, and systolic blood pressure was measured by the tail-cuff method. Vascular structure was studied in small arteries mounted on a wire myograph. Treatment with bosentan did not result in a significant change in systolic blood pressure or in the structure of small coronary, renal cortical, mesenteric, or femoral arteries in 1K, 1C or in 2K, 1C hypertensive rats. In conclusion, modest (twofold) elevations of endothelin-1 gene expression in blood vessels in renovascular hypertension are not associated with hypotensive responses or regression of vascular hypertrophy during treatment with endothelin antagonists in contrast to what is found in deoxycorticosterone acetate salt hypertensive rats, which exhibit very dramatic increases in endothelin-1 expression (five-to eightfold) and do respond to endothelin antagonism with blood pressure lowering and regression of vascular hypertrophy. These small elevations of vascular endothelin-1 gene expression thus do not appear to indicate the presence of an endothelin component in blood pressure elevation in renovascular hypertension in rats.

Dietary Essential Polyunsaturated Fatty Acids and Blood Pressure

Physiology ◽  
1989 ◽  
Vol 4 (2) ◽  
pp. 64-68
Author(s):  
JAF Tresguerres ◽  
V Lahera ◽  
MV Cachofeiro
Keyword(s):  
Blood Pressure ◽  
Fatty Acids ◽  
Cardiovascular Diseases ◽  
Polyunsaturated Fatty Acids ◽  
Reduce Blood Pressure ◽  
Experimental Models ◽  
High Intake ◽  
Beneficial Effects ◽  
Vasoactive Factors

A high intake of polyunsaturated fatty acids has been reported as being able to reduce blood pressure and to protect against several cardiovascular diseases. These effects have been observed in hypertensive and normotensive humans and in experimental models of hypertension. Prostaglandins have been considered responsible for these beneficial effects, although other vasoactive factors could also be involved.

scholarly journals Atorvastatin improves tubular status in non-diabetic patients with chronic kidney disease - placebo controlled, randomized, cross-over study.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Marcin Renke ◽  
Leszek Tylicki ◽  
Przemysław Rutkowski ◽  
Alexander Neuwelt ◽  
Wojciech Larczyński ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Damage ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Experimental Models ◽  
Diabetic Patients ◽  
Tubular Damage ◽  
Converting Enzyme Inhibitors ◽  
Raas Blockade

There is evidence that dyslipidemia is associated with chronic kidney disease (CKD) and it has been implicated in the progression of renal damage. Optimal management of dyslipidemia should therefore lead to renal benefits. A number of experimental models demonstrate a beneficial effect of statins in ameliorating renal damage. However, the exact mechanism by which statins protect against renal damage remains unclear. In a placebo-controlled, randomized, cross-over study we evaluated the influence of atorvastatin (ATO) 40 mg/day added to the renin-angiotensin-aldosterone systeme (RAAS) blockade on proteinuria and surrogate biomarkers of tubular damage or injury in 14 non-diabetic patients with proteinuria (0.4-1.8 g per 24 h) with normal or declined kidney function (eGFR 55-153 ml/min). In the eight-week run-in period, therapy using angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin II subtype 1 receptor antagonists (ARB) was adjusted to achieve a blood pressure below 130/80 mm Hg. Next, patients were randomly assigned to one of two treatment sequences: ATO/washout/placebo or placebo/washout/ATO. Clinical evaluation and laboratory tests were performed at the randomization point and after each period of the study. The primary end point of this study was a change in proteinuria measured as 24-h urine protein excretion (DPE). Secondary end points included urine N-acetyl-β-D-glucosaminidase (NAG) and α1-microglobulin (α1m) excretion. The ATO therapy significantly reduced urine excretion of α₁m (p=0.033) and NAG (p=0.038) as compared to placebo. There were no differences in proteinuria, blood pressure, eGFR and serum creatinine between the ATO and placebo groups. Atorvastatin treatment is safe and improves biomarkers of tubular damage or injury in non-diabetic patients with CKD.

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