The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling

Smith, Delaney

doi:10.1007/s00285-023-01891-y

Cited by 6 publications

(19 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The parameter changes made to simulate hypertension were based largely on the hypertensive female (virgin) rat results in Veiras et al [37], where the effects of angiotensin II-induced hypertension (a common protocol used in experimental models to induce hypertension [35][36][37][38]) on female and male rats was investigated. Additionally, we made some parameter changes using the results from Abreu et al [49], who investigated renal Na + and aquaporin (AQP) transporters in hypertensive virgin and mid-pregnant rats.…”

Section: Simulating Hypertension In Female and Pregnant Ratsmentioning

confidence: 99%

“…The kidneys play an essential role in long-term blood pressure control. Altered renal function in a rat occurs during hypertension [35][36][37][38]. Specifically, in female rats, chronic hypertension has been shown to decrease Na + transporter activity in the proximal segments as well as increase Na + transporter activity in the distal segments [37].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of pregnancy and hypertension on kidney function in female rats: Modeling and functional implications

Stadt

West

2023

PLoS ONE

View full text Add to dashboard Cite

Throughout pregnancy, the kidneys undergo significant adaptations in morphology, hemodynamics, and transport to achieve the volume and electrolyte retention required to support a healthy pregnancy. Additionally, during pregnancies complicated by chronic hypertension, altered renal function from normal pregnancy occurs. The goal of this study is to analyze how inhibition of critical transporters affects gestational kidney function as well as how renal function is affected during chronic hypertension in pregnancy. To do this, we developed epithelial cell-based multi-nephron computational models of solute and water transport in the kidneys of a female rat in mid- and late pregnancy. We simulated the effects of key individual pregnancy-induced changes on renal Na+ and K+ transport: proximal tubule length, Na+/H+ exchanger isoform 3 (NHE3) activity, epithelial Na+ channel activity (ENaC), K+ secretory channel expression, and H+-K+-ATPase activity. Additionally, we conducted simulations to predict the effects of inhibition and knockout of the ENaC and H+-K+-ATPase transporters on virgin and pregnant rat kidneys. Our simulation results predicted that the ENaC and H+-K+-ATPase transporters are essential for sufficient Na+ and K+ reabsorption during pregnancy. Last, we developed models to capture changes made during hypertension in female rats and considered what may occur when a rat with chronic hypertension becomes pregnant. Model simulations predicted that in hypertension for a pregnant rat there is a similar shift in Na+ transport from the proximal tubules to the distal tubules as in a virgin rat.

show abstract

Section: Simulating Hypertension In Female and Pregnant Ratsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of pregnancy and hypertension on kidney function in female rats: Modeling and functional implications

Stadt

West

2023

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…The RAS model referenced in this work is taken directly from Smith and Layton (2023). It considers both the systemic and the intrarenal RAS via a systemic compartment and four intrarenal tissue compartments: the glomerular compartment, the peritubular compartment, the tubular compartment, and the vasculature compartment.…”

Section: Ras Modelmentioning

confidence: 99%

“…An objective of this study is to investigate the validity of this hypothesis. This is accomplished by coupling a model of the rat intrarenal RAS that incorporates the aforementioned feedback loops Smith and Layton (2023) to a pharmacokinetic (PK) model of an ARB to create a comprehensive pharmacokinetic/pharmacodynamic (PK/PD) model. In particular, we simulate and compare Ang II infusion experiments with and without ARB treatment to investigate two clinically relevant questions: (i) Which Ang II accumulation mechanism, enhanced AT1R-mediated uptake (UPTK) or increased endogenous production (PROD), is the primary target of ARB treatment?…”

Section: Introductionmentioning

confidence: 99%

“…This is because the relationship between drug dosage and Ang II-AT1R binding is rarely, if ever, explicitly experimentally quantified. Instead, a PK model describing Losartan and its metabolite EXP3174 is desirable, as it can be coupled to our previous RAS model (Smith and Layton, 2023) via the drug's known AT1R binding properties. Such a model has previously been developed to study gastric emptying in humans (Karatza and Karalis, 2020).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of angiotensin-receptor blockers on intrarenal renin-angiotensin system activity in hypertension: A PK/PD modelling study

Smith

2023

Preprint

Self Cite

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) is a primary regulator of volume homeostasis and blood pressure, whose over-activation is commonly associated with hypertension. Indeed, medications that target the RAS are generally effective in reducing blood pressure. However, more can be learned about how these medications influence the intrarenal RAS. Angiotensin-receptor blockers (ARBs) in particular have been shown to exert different effects on the intrarenal and systemic RASs in various experimental models of hypertension. In rats chronically infused with angiotensin II (Ang II), ARBs consistently prevent intrarenal, but not systemic Ang II levels from rising. The former effect is sufficient in pre- venting the development of hypertension. The regulation of intrarenal RAS, independently of the systemic RAS, by ARBs has been hypoth- esized to be mediated by the inhibition of all positive feedback loops inherent to the intrarenal RAS, also known as the "key point break- down effect." To investigate the validity of this hypothesis, we developed a PK/PD model of the ARB Losartan that considers the kidney, and applied the model to study how this class of medication influences intrarenal RAS activity and consequently blood pressure regulation in male rats. Simulations indicate that ARBs more effectively inhibit the activation of the intrarenal RAS because, unlike in the plasma, this pro- cess relies on the accumulation of cell-associated Ang II. We hypothesize that it is by blocking this intracellular uptake pathway, and restrict- ing Ang II to extracellular regions of the kidney where the peptide cannot initiate downstream signalling, that Losartan normalizes blood pressure. While the key point break down effect assists in this response, it alone is not sufficient. Our results highlight the intrarenal RAS as the key pharmacological target of ARB treatment and emphasize the importance of this local tissue RAS in the development of hypertension.

show abstract

Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway

Jena,

Kaur,

Singh

et al. 2024

Mol Neurobiol

View full text Add to dashboard Cite

The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling

Cited by 6 publications

References 101 publications

Effect of pregnancy and hypertension on kidney function in female rats: Modeling and functional implications

Effect of pregnancy and hypertension on kidney function in female rats: Modeling and functional implications

Impact of angiotensin-receptor blockers on intrarenal renin-angiotensin system activity in hypertension: A PK/PD modelling study

Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway

Contact Info

Product

Resources

About