Molecular Mechanisms of Renal Blood Flow Autoregulation

Burke, Marilyn; Pabbidi, Mallikarjuna R.; Farley, Jerry M.; Roman, Richard J.

doi:10.2174/15701611113116660149

Cited by 129 publications

(90 citation statements)

References 208 publications

(218 reference statements)

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“…30,31 That local AGT expression contributes to intrarenal Ang II is not surprising because it has been noted that at some renal sites, tubular expression of AGT is greater when compared with liver expression 32 and AGT expression has been observed throughout the entire nephron. 33 Although the residual kidney AGT that remains after ≈90% reductions of circulating AGT was critical in maintaining renal function during a severe RAAS challenge, it was unimportant in the maintenance of hypertension because GalNAc AGT ASO treatment was effective in BP lowering.…”

Section: Discussionmentioning

confidence: 99%

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Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

et al. 2017

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566T he discovery and development of renin-angiotensin-aldosterone system (RAAS) inhibitors have established a role of angiotensin II (Ang II) in disease, leading to therapies that are the foundation of treatment for cardiovascular and renal diseases.1 Yet, as effective as RAAS inhibitors have been in the clinic, there is a need to improve the efficacy, safety, and tolerability of this drug class.Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) elicit compensatory pathways resulting in angiotensin reactivation and aldosterone breakthrough such that plasma Ang II and aldosterone return to pretreatment levels or higher. 2,3 This phenomenon may contribute to the suboptimal efficacy of RAAS blockade in patients with resistant hypertension and heart failure. 4,5 Noncanonical pathways of Ang II generation and intracellular RAAS signaling are considered important mechanisms that limit the therapeutic potential of this drug class. 6 AGT (angiotensinogen) is the source of all downstream angiotensin metabolites. The liver is the principal source of circulating AGT, 7-9 although extrahepatic sites of expression, such as in the kidney, have been implicated in the regulation of blood pressure (BP), sodium, and water homeostasis. 10 More aggressive RAAS inhibition, as attempted by combining different classes of RAAS inhibitors, has demonstrated poor clinical utility due in part to adverse effects, such as hyperkalemia, hypotension, and acute renal failure.11 A current hypothesis is that such untoward effects are because of excessive renal RAAS inhibition. 12 Thus, a more effective therapeutic strategy would (1) work upstream of the RAAS enzymes and receptors, thereby avoiding compensatory mechanisms and intracrine signaling that limit therapeutic efficacy, and (2) have limited kidney activity, thereby providing the benefits of aggressive RAAS suppression without provoking renal complications.To this end, we developed a liver-selective AGT antisense oligonucleotide (ASO) that produced potent and durable reductions of liver AGT expression after systemic administration. Liver targeting is achieved by covalent linkage of triantennary N-acetylgalactosamine (GalNAc), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor, to an ASO. This GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes Abstract-Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N...

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Section: Discussionmentioning

confidence: 99%

Section: 8mentioning

confidence: 99%

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

et al. 2017

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“…Increased NO production and inflammatory response attenuate renal autoregulation [23]. When these occur in critically ill patients, the renal blood flow is difficult to stabilize with damaged renal autoregulation after variations in BP.…”

Section: Discussionmentioning

confidence: 99%

Relationship Between Short-Term Blood Pressure Variability and Incidence of Acute Kidney Injury in Critically Ill Patients

Xie

Liao

Yin

et al. 2017

Kidney Blood Press Res

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Background/Aims: Blood pressure (BP) variability is associated with cardiovascular events, and cerebral and renal damage. The aim of this study was to investigate any potential relationship between short-term BP variability and incidence of acute onset conditions, such as acute kidney injury (AKI), in critically ill patients. Methods: BP was monitored to analyze its variability in critically ill patients in present study. Short-term BP variability was assessed as average real variability (ARV), standard deviation (SD) and coefficient of variation (CV) of 24-hour BP. Results: A total of 565 patients were included, 41.2% (n=233) of which presented with AKI after admission (AKI stage I, n = 94; stage II, n = 37; stage III, n = 102). The mean APACHE II score was 21.5 for all patients. ARV of 24 h systolic BP was significantly higher in patients with AKI (p<0.001). This association remained (p=0.006) after adjustment for potential confounders. The incidence of AKI increased with the ARV from 14.0% (ARV ≤6 mmHg) to 73.9% (ARV >14 mmHg). A weak association was also found between BP variability and hospital mortality in critically ill patients. Conclusion: BP variability is correlated with the incidence of AKI in critically ill patients.

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“…Despite the evidence that intrarenal Ang II contributes to hypertension or renal disease [31, 133], renal homeostatic functions required for maintenance of renal blood flow and GFR are in part regulated by Ang II [134, 135]. That all RAAS components have been identified throughout the entire nephron is suggestive of an essential role of intrarenal RAAS for volume and electrolyte homeostasis [136].…”

Section: 0 Direct Renin Inhibitors: An Incomplete Storymentioning

confidence: 99%

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

Ferrario

Mullick

2017

Pharmacological Research

101

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A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1-7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase –the primary angiotensin II forming enzyme in the human heart–, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.

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Molecular Mechanisms of Renal Blood Flow Autoregulation

Cited by 129 publications

References 208 publications

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

Relationship Between Short-Term Blood Pressure Variability and Incidence of Acute Kidney Injury in Critically Ill Patients

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

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