scholarly journals Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1600-1612
Author(s):  
Dominique M. Bovée ◽  
Liwei Ren ◽  
Estrellita Uijl ◽  
Marian C. Clahsen-van Groningen ◽  
Richard van Veghel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Mean Arterial Pressure ◽  
Kidney Disease ◽  
Arterial Pressure ◽  
Small Interfering Rna ◽  
Ang Ii ◽  
Blood Pressure Lowering Effect ◽  
Independent Manner ◽  
Interfering Rna

Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) lowers blood pressure, but its effectiveness in hypertensive chronic kidney disease is unknown. Considering that the kidney may generate its own AGT, we assessed the effectiveness of liver-targeted AGT siRNA in the 5/6th Nx (5/6th nephrectomy) rat—a hypertensive chronic kidney disease model. Five weeks after 5/6th Nx (baseline), rats were subjected to vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril. Baseline mean arterial pressure was 160±6 mm Hg. Over the course of 4 weeks, mean arterial pressure increased further by ≈15 mm Hg during vehicle treatment. This rise was prevented by AGT siRNA. Losartan reduced mean arterial pressure by 37±6 mm Hg and increased plasma Ang (angiotensin) II. Both AGT siRNA and captopril suppressed these effects of losartan, suggesting that its blood pressure–lowering effect relied on stimulation of vasodilator Ang II type 2 receptors by high Ang II levels. Proteinuria and cardiac hypertrophy increased with vehicle, and these increases were comparably abrogated by all treatments. No intervention improved glomerular filtration rate, while siRNA and losartan equally diminished glomerulosclerosis. AGT siRNA±losartan reduced plasma AGT by >95%, and this was accompanied by almost complete elimination of Ang II in kidney and heart, without decreasing renal AGT mRNA. Multiple linear regression confirmed both mean arterial pressure and renal Ang II as independent determinants of proteinuria. In conclusion, AGT siRNA exerts renoprotection in the 5/6th Nx model in a blood pressure–independent manner. This relies on the suppression of renal Ang II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human chronic kidney disease.

scholarly journals Mean Arterial Pressure and Chronic Kidney Disease Progression in the CKiD Cohort

Hypertension ◽  
2021 ◽  
Author(s):  
Janis M. Dionne ◽  
Shuai Jiang ◽  
Derek K. Ng ◽  
Joseph T. Flynn ◽  
Mark M. Mitsnefes ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Mean Arterial Pressure ◽  
Kidney Disease ◽  
Arterial Pressure ◽  
Disease Progression ◽  
Ambulatory Blood Pressure ◽  
Blood Pressure Monitoring ◽  
Risk Of Progression ◽  
Kidney Disease Progression

Consensus blood pressure guidelines vary in their recommended ambulatory blood pressure targets for children with chronic kidney disease (CKD) because of limited research in this area. We analyzed longitudinal ambulatory blood pressure monitoring data from 679 children with moderate CKD enrolled in the observational CKiD (Chronic Kidney Disease in Children) cohort by time-varying mean arterial pressure (MAP) percentile categories based on the highest wake or sleep MAP percentile. Analyses were stratified by nonglomerular and glomerular diagnoses, with 3 models constructed: unadjusted, adjusted for age, sex, and race, and additional adjustment for proteinuria. The outcome of interest was time to renal replacement therapy or 50% decline in baseline renal function. We found that among children with nonglomerular CKD, MAP percentile was not associated with accelerated disease progression risk until after 4 years of follow-up at which point a high MAP (>90th percentile) was associated with a higher risk of progression to the composite end point (HR, 1.88 [CI, 1.03–3.44]). Among those with glomerular CKD, differential risk for progression began from baseline with the highest risk in those with MAP >90th percentile (HR, 3.23 [CI, 1.34–7.79]). These relationships were attenuated somewhat after adjustment for level of proteinuria, but the trend for higher MAP being associated with higher risk of progression remained significant. Thus, in children with CKD, having ambulatory wake or sleep MAP >90th percentile was associated with higher risk of kidney disease progression with the highest levels of MAP associated with the greatest risk of progression. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00327860

Abstract 319: Intermedin Attenuates Vascular Calcification by Upregulating Klotho via CRLR/RAMP3 Receptor Complex and cAMP/PKA Signaling Pathway in Rats With Chronic Kidney Disease

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jin-Rui Chang ◽  
Yue-Long Hou ◽  
Wei-Wei Lu ◽  
Jin-Sheng Zhang ◽  
Yan-Rong Yu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Signaling Pathway ◽  
Vascular Calcification ◽  
Small Interfering Rna ◽  
Calcium Deposition ◽  
Alp Activity ◽  
Klotho Protein ◽  
Interfering Rna

Vascular calcification (VC) is highly associated with increased morbidity and mortality in patients with advanced chronic kidney disease(CKD). We previously reported that paracrine/autocrine factor intermedin (IMD) could protect against VC. In the present study we assessed the hypothesis that IMD inhibits VC by upregulating klotho protein. VC in CKD rat was induced by 5/6 nephrectomy plus vitamin D 3 administration and vascular smooth muscle cells (VSMCs) calcification was induced by calcifying media containing β -glycerophosphate and CaCl 2 . IMD (100 ng kg -1 h -1 ) was systemically administered by a mini-osmotic pump. CKD rat aortas showed lower IMD content and increased expression of its receptors (calcitonin receptor-like receptor,CRLR/receptor activity-modifying protein 3, RAMP3), along with increased aortic alkaline phosphatase (ALP) activity and calcium deposition. In vivo administration of IMD significantly reduced aortic ALP activity and calcium deposition in CKD rats when compared with vehicle treatment, which was further confirmed in cultured VSMCs. Concurrently, the loss of smooth muscle lineage markers and klotho protein in aortas was rescued by administering IMD to CKD rats with VC. However, the inhibitory effects of IMD on VC were abolished upon pre-treatment with small interfering RNA to reduce klotho. Moreover, the increased effects of IMD on klotho were abolished upon pretreatment with small interfering RNA to reduce its receptors or with PKA inhibitor H89. These results demonstrated that IMD attenuates VC by upregulating klotho via CRLR/RAMP3-cAMP/PKA signaling pathway in rat with CKD. IMD is an important paracrine/autocrine protective factor for VC.

Control of blood pressure and hindlimb conductance during hemorrhage in conscious renal hypertensive rabbits

1995 ◽  
Vol 268 (6) ◽  
pp. H2302-H2310 ◽  
Author(s):  
G. Weichert ◽  
C. A. Courneya
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Nervous System ◽  
Autonomic Nervous System ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Similar Pattern ◽  
Ang Ii ◽  
Autonomic Nervous

We examined the response to hemorrhage in conscious normotensive and hypertensive rabbits under control conditions and during efferent blockade of 1) the hormones vasopressin (AVP) and angiotensin II (ANG II), 2) the autonomic nervous system, and 3) autonomic and hormonal inputs. We recorded mean arterial pressure, heart rate, and hindlimb conductance. The response to hemorrhage was unchanged with hormonal blockade alone. Blockade of the autonomic nervous system caused a faster rate of blood pressure decline, but the rate of decrease in hindlimb conductance was maintained at control levels. Blocking the autonomic nervous system and the hormones resulted in rapid blood pressure decline and an increase in hindlimb conductance. Although the three types of efferent blockade had a similar pattern of effects in normotensive and hypertensive rabbits, hypertensive rabbits exhibited less cardiovascular support during hemorrhage than normotensive rabbits. During hemorrhage, hypertensive rabbits had an attenuation of hindlimb vasoconstriction, a reduction in the heart rate-mean arterial pressure relationship, and reduced ability to maintain blood pressure compared with normotensive rabbits.

scholarly journals Angiotensin II utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake

2011 ◽  
Vol 301 (4) ◽  
pp. R1169-R1176 ◽  
Author(s):  
Amy K. L. Banes-Berceli ◽  
Hind Al-Azawi ◽  
Daniel Proctor ◽  
Harvey Qu ◽  
Dominic Femminineo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Janus Kinase ◽  
Ang Ii ◽  
Physiological Control ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Low Salt

Janus kinase (JAK) 2 is activated by ANG II in vitro and in vivo, and chronic blockade of JAK2 by the JAK2 inhibitor AG-490 has been shown recently to attenuate ANG II hypertension in mice. In this study, AG-490 was infused intravenously in chronically instrumented rats to determine if the blunted hypertension was linked to attenuation of the renal actions of ANG II. In male Sprague-Dawley rats, after a control period, ANG II at 10 ng·kg−1·min−1 was infused intravenously with or without AG-490 at 10 ng·kg−1·min−1 iv for 11 days. ANG II infusion (18 h/day) increased mean arterial pressure from 91 ± 3 to 168 ± 7 mmHg by day 11. That response was attenuated significantly in the ANG II + AG-490 group, with mean arterial pressure increasing only from 92 ± 5 to 127 ± 3 mmHg. ANG II infusion markedly decreased urinary sodium excretion, caused a rapid and sustained decrease in glomerular filtration rate to ∼60% of control, and increased renal JAK2 phosphorylation; all these responses were blocked by AG-490. However, chronic AG-490 treatment had no effect on the ability of a separate group of normal rats to maintain normal blood pressure when they were switched rapidly to a low-sodium diet, whereas blood pressure fell dramatically in losartan-treated rats on a low-sodium diet. These data suggest that activation of the JAK/STAT pathway is critical for the development of ANG II-induced hypertension by mediating its effects on renal sodium excretory capability, but the physiological control of blood pressure by ANG II with a low-salt diet does not require JAK2 activation.

PLASMA ADIPONECTIN AND MEAN ARTERIAL PRESSURE WERE ASSOCIATED WITH LV MASS INDEX IN CHRONIC KIDNEY DISEASE

2008 ◽  
Vol 9 (1) ◽  
pp. 125
Author(s):  
K. Badjranadha ◽  
A. Santoso ◽  
R. Widiana ◽  
J.S. Loekman ◽  
W. Sudana ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Mean Arterial Pressure ◽  
Kidney Disease ◽  
Arterial Pressure ◽  
Plasma Adiponectin ◽  
Lv Mass

Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted SHR

2003 ◽  
Vol 284 (1) ◽  
pp. R164-R173 ◽  
Author(s):  
Shigefumi Nakamura ◽  
David B. Averill ◽  
Mark C. Chappell ◽  
Debra I. Diz ◽  
K. Bridget Brosnihan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Angiotensin Receptors ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Blood Pressure Lowering Effect ◽  
Blood Pressure Elevation ◽  
Spontaneously Hypertensive

This study evaluated the contribution of angiotensin peptides acting at various receptor subtypes to the arterial pressure and heart rate of adult 9-wk-old male conscious salt-depleted spontaneously hypertensive rats (SHR). Plasma ANG II and ANG I in salt-depleted SHR were elevated sevenfold compared with peptide levels measured in sodium-replete SHR, whereas plasma ANG-(1–7) was twofold greater in salt-depleted SHR compared with salt-replete SHR. Losartan (32.5 μmol/kg), PD-123319 (0.12 μmol · kg−1 · min−1), [d-Ala7]ANG-(1–7) (10 and 100 pmol/min), and a polyclonal ANG II antibody (0.08 mg/min) were infused intravenously alone or in combination. Combined blockade of AT2 and AT(1–7) receptors significantly increased the blood pressure of losartan-treated SHR (+15 ± 1 mmHg; P < 0.01); this change did not differ from the blood pressure elevation produced by the sole blockade of AT(1–7) receptors (15 ± 4 mmHg). On the other hand, sole blockade of AT2 receptors in losartan-treated SHR increased mean arterial pressure by 8 ± 1 mmHg ( P < 0.05 vs. 5% dextrose in water as vehicle), and this increase was less than the pressor response produced by blockade of AT(1–7) receptors alone or combined blockade of AT(1–7) and AT2 receptors. The ANG II antibody increased blood pressure to the greatest extent in salt-depleted SHR pretreated with only losartan (+11 ± 2 mmHg) and to the least extent in salt-depleted SHR previously treated with the combination of losartan, PD-123319, and [d-Ala7]ANG-(1–7) (+7 ± 1 mmHg; P < 0.01). Losartan significantly increased heart rate, whereas other combinations of receptor antagonists or the ANG II antibody did not alter heart rate. Our results demonstrate that ANG II and ANG-(1–7) act through non-AT1receptors to oppose the vasoconstrictor actions of ANG II in salt-depleted SHR. Combined blockade of AT2 and AT(1–7) receptors and ANG II neutralization by the ANG II antibody reversed as much as 67% of the blood pressure-lowering effect of losartan.

Renal inflammation is modulated by potassium in chronic kidney disease: possible role of Smad7

2007 ◽  
Vol 293 (4) ◽  
pp. F1123-F1130 ◽  
Author(s):  
Wansheng Wang ◽  
Liliana Soltero ◽  
Ping Zhang ◽  
Xiao R. Huang ◽  
Hui Y. Lan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intracellular Signaling ◽  
Basal Diet ◽  
Sprague Dawley ◽  
Blood Pressure Lowering Effect ◽  
High Potassium ◽  
Renal Inflammation ◽  
Potassium Supplementation

High-potassium diets have been shown to be beneficial in cardiovascular disease partly because of a blood pressure-lowering effect. The effect of potassium on inflammation has not been studied. We investigated the influence of potassium supplementation on the degree of renal inflammation and the intracellular signaling mechanisms that could mediate inflammation in chronic kidney disease (CKD). CKD was created in male Sprague-Dawley rats by subtotal nephrectomy. Two groups of CKD rats were pair fed with diets containing 2.1% potassium (potassium-supplemented diet) or 0.4% potassium (basal diet). Body weight, blood pressure, and blood and urine electrolytes were measured biweekly. The animals were euthanized at week 8, and the remnant kidneys were analyzed by histology, immunohistochemistry, Western blotting, and real-time quantitative PCR. In the CKD pair-fed groups, blood potassium concentration did not differ significantly, but blood pressure was lower in the potassium-supplemented group. Compared with the basal diet, potassium supplementation decreased renal tubulointerstitial injury and suppressed renal inflammation as evidenced by decreased macrophage infiltration, lower expression of inflammatory cytokines, and decreased NF-κB activation. These renoprotective effects were associated with downregulation of renal transforming growth facto-β, upregulation of renal Smad7, and lower blood pressure. Our results show that potassium supplementation can reduce renal inflammation and hence, could modulate the progression of kidney injury in CKD.

scholarly journals SEX DIFFERENCES IN BLOOD PRESSURE RESPONSE TO CONTINUOUS ANG II INFUSION: ARE ONLY SEX HORMONES TO BLAME?

2021 ◽  
Author(s):  
Florencia Dadam ◽  
Andrea Godino ◽  
Laura Vivas ◽  
Ximena E Caeiro
Keyword(s):  
Blood Pressure ◽  
Sex Differences ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Testosterone Propionate ◽  
Chromosome Complement ◽  
Ang Ii ◽  
Male Mice ◽  
Hormonal Effects ◽  
Xx Males

To investigate the involvement of the sex chromosome complement (SCC), organizational and activational hormonal effects in changes in mean arterial pressure during acute Ang II infusion, we used gonadectomized (GDX) mice of the "four core genotypes" model, which dissociates the effect of gonadal sex and SCC, allowing comparisons of sexually dimorphic traits between XX and XY females as well as XX and XY males. Additionally, β-estradiol and testosterone propionate (2ug/g) were daily injected for 4 days to evaluate activational hormonal effects. Statistical analysis of the changes in mean arterial pressure revealed an interaction of SCC, organizational and activational hormonal effects during Ang II infusion {F(7,39=2,60 p<0.01)}. Our results indicate that, in absence of activational hormonal effects, interaction between the SCC and organizational hormonal action differentially modulates changes in arterial pressure. In GDX mice without hormone replacement, Ang II infusion resulted in an increase in mean arterial pressure in XX-male, XX-female and XY-female mice, while no changes were observed in XY-male mice. Furthermore, β-estradiol replacement (GDX+E2 group) resulted in a decrease in blood pressure in XX-males, XX-females and XY-females (indicating an activational β-estradiol effect), while no changes were observed in the XY-male group. Moreover, testosterone propionate replacement (GDX+TP group) showed a greater increase in blood pressure in XY-male mice than in XX-males and XX-females, demonstrating an activational hormonal effect of testosterone in XY-male mice. Our data isolates and highlights the contribution and interaction of SCC, activational and organizational hormonal effects in sex differences in Ang II blood pressure regulation.

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