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

Stadt, Melissa; West, Crystal A.

doi:10.1101/2022.12.15.520674

Cited by 2 publications

(2 citation statements)

References 103 publications

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“…Indeed, this whole-body K + model may be extended to consider sex differences as well as unique physiological states in females that undergo major changes in K + regulation such as pregnancy and lactation [37,40,45].…”

Section: Model Limitations and Future Workmentioning

confidence: 99%

A modeling analysis of whole-body potassium regulation on a high potassium diet: Proximal tubule and tubuloglomerular feedback effects

Stadt,

Layton

2023

Preprint

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Potassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, as well as hormone secretion and action. Indeed, maintaining K+balance is critical for normal cell function, as too high or too low K+levels can have serious and potentially deadly health consequences. K+homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K+intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na+-K+-ATPase uptake, and hormone and electrolyte impacts on renal K+handling. We recently developed a mathematical model of whole-body K+regulation to unravel the individual impacts of regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high K+diet. We conducted model simulations and sensitivity analyses to unravel how these renal alterations impact whole-body K+regulation. Our results suggest that the reduced proximal tubule K+reabsorption under a high K+diet could achieve K+balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K+excretion. Model predictions quantify the sensitivity of K+regulation to various levels of proximal tubule K+reabsorption adaptation and tubuloglomerular feedback. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, intracellular K+stores can exceed normal range under a high K+diet.

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Section: Model Limitations and Future Workmentioning

confidence: 99%

A modeling analysis of whole-body potassium regulation on a high potassium diet: Proximal tubule and tubuloglomerular feedback effects

Stadt,

Layton

2023

Preprint

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“…Furthermore, people with hypertension often suffer from other diseases such as diabetes, which also impact kidney function (69,70). Understanding kidney function in pregnancy (71,72) and hypertension may lead to better treatment options for gestational hypertension and preeclampsia.…”

Section: A Widely Utilized Experimental Model Of Hypertension Is the ...mentioning

confidence: 99%

Modeling Sex Differences in the Effects of Diuretics in Renal Epithelial Transport during Angiotensin II-induced Hypertension

Zheng,

Layton

2023

Preprint

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Chronic angiotensin II (AngII) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females, perhaps unexpectedly, given the rodent kidney, which plays a key role in blood pressure regulation, exhibit marked sex differences. Those sex differences include morphology, hemodynamics, and, under healthy (undrugged) conditions, solute and electrolyte transporter abundance. Notably, compared to the male rat nephron, the female rat nephron exhibits lower Na+/H+exchanger 3 (NHE3) activity along the proximal tubule, but higher Na+transporter activities along the distal segments. AngII infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+transport capacity downstream, to different extents in the two sexes. The goals of this study are (i) to understand how the sexually dimorphic responses differentially impact segmental electrolyte transport following a 14- day AngII infusion, and (ii) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. To achieve those goals, we developed sex-specific computational models of renal epithelial transport of electrolytes and water. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with a stronger effect in males. Due to the downstream shift of Na+transport load in hypertension, all three diuretic classes are predicted to induce stronger natriuretic and diuretic effects under hypertension compared to normotension, especially in females.New and NoteworthySex differences in the prevalence of hypertension are found in humans and animal models. The kidney, which plays an important role in blood pressure regulation, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport. Simulations results also explain sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics.

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

Cited by 2 publications

References 103 publications

A modeling analysis of whole-body potassium regulation on a high potassium diet: Proximal tubule and tubuloglomerular feedback effects

A modeling analysis of whole-body potassium regulation on a high potassium diet: Proximal tubule and tubuloglomerular feedback effects

Modeling Sex Differences in the Effects of Diuretics in Renal Epithelial Transport during Angiotensin II-induced Hypertension

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