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

Stadt, Melissa; West, Crystal A.

doi:10.1371/journal.pone.0279785

Cited by 10 publications

(3 citation statements)

References 85 publications

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“…The homeostasis of these electrolytes is altered during pregnancy, lactation, and dietary restriction, as well as in diseases such as diabetes and chronic kidney disease. To utilize the present model for in silico studies of how the kidney adapts in terms of Ca 2+ and Mg 2+ transport under these physiological and pathophysiological conditions, one can combine the model with computational models of kidney function for a pregnant rat [54,55], a diabetic rat [56][57][58], and a nephrectomized rat [8,59]. The resulting models may provide insights into altered renal Ca 2+ and Mg 2+ transport under these conditions.…”

Section: Discussionmentioning

confidence: 99%

Magnesium and Calcium Transport along the Male Rat Kidney: Effect of Diuretics

Dutta,

Layton

2024

MCA

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Calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function. The kidneys play an important role in maintaining the homeostasis of these cations. Their reabsorption along the nephron is dependent on distinct trans- and paracellular pathways and is coupled to the transport of other electrolytes. Notably, sodium (Na+) transport establishes an electrochemical gradient to drive Ca2+ and Mg2+ reabsorption. Consequently, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ and Mg2+ transport. One such condition is the administration of diuretics, which are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. While the pharmacological targets of diuretics typically directly mediate Na+ transport, they also indirectly affect renal Ca2+ and Mg2+ handling through alterations in the electrochemical gradient. To investigate renal Ca2+ and Mg2 handling and how those processes are affected by diuretic treatment, we have developed computational models of electrolyte transport along the nephrons. Model simulations indicate that along the proximal tubule and thick ascending limb, the transport of Ca2+ and Mg2+ occurs in parallel with Na+, but those processes are dissociated along the distal convoluted tubule. We also simulated the effects of acute administration of loop, thiazide, and K-sparing diuretics. The model predicted significantly increased Ca2+ and Mg2+ excretions and significantly decreased Ca2+ and Mg2+ excretions on treatment with loop and K-sparing diuretics, respectively. Treatment with thiazide diuretics significantly decreased Ca2+ excretion, but there was no significant alteration in Mg2+ excretion. The present models can be used to conduct in silico studies on how the kidney adapts to alterations in Ca2+ and Mg2+ homeostasis during various physiological and pathophysiological conditions, such as pregnancy, diabetes, and chronic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Magnesium and Calcium Transport along the Male Rat Kidney: Effect of Diuretics

Dutta,

Layton

2024

MCA

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show abstract

“…The homeostasis of these electrolytes is altered pregnancy, lactation, and dietary restriction, as well as in diseases such as diabetes and chronic kidney disease. To utilize the present model for in silico studies of how the kidney adapts in terms of Ca 2+ and Mg 2+ transport under these physiological and pathophysiological conditions, one can combine the model with computational models of kidney function for a pregnant rat [47,48], a diabetic rat [49][50][51], a nephrectomized rat [9,52], or a whole-kidney model [53][54][55]. The resulting models may provide insights into altered renal Ca 2+ and Mg 2+ transport under these conditions.…”

Section: Discussionmentioning

confidence: 99%

Modeling magnesium and calcium transport along male rat kidney and the effects of diuretics

Dutta,

Layton

2023

Preprint

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Calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function. The kidneys play an important role in maintaining the homeostasis of these cations. Their reabsorption along the nephron is dependent on distinct trans- and paracellular pathways, and is coupled to the transport of other electrolytes. Notably, sodium (Na+) transport establishes an electrochemical gradient to drive Ca2+reabsorption. Consequently, alterations in renal Na+handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+transport. One such condition is the administration of diuretics, which are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. While the pharmacological targets of diuretics typically directly mediate Na+transport, they also indirectly affect renal Ca2+and Mg2+handling, i.e., by establishing a prerequisite electrochemical gradient. Thus, substantial alterations in divalent cation handling can be expected following diuretic treatment. To investigate renal Ca2+and Mg2handling, and how those processes are affected by diuretics treatment, we have developed sex-specific computational models of electrolyte transport along the nephrons. Model simulations indicate that along the proximal tubule and thick ascending limb, the transport of Ca2+and Mg2+occusr in parallel with Na+, but those processes are dissociated along the distal convoluted tubule. We also simulated the effects of acute administration of loop, thiazide, and K-sparing diuretics. The model predicted significantly increased Mg2+excretion, no significant alteration in Mg2+excretion, and significantly decreased Mg2+excretion on treatment with loop, thiazide, and K-sparing diuretics, respectively, in agreement with experimental studies. The present models can be used to conductin silicostudies on how the kidney adapts to alterations in Ca2+and Mg2+homeostasis during various physiological and pathophysiological conditions, such as pregnancy, diabetes, and chronic kidney disease.

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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: Discussionmentioning

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 10 publications

References 85 publications

Magnesium and Calcium Transport along the Male Rat Kidney: Effect of Diuretics

Magnesium and Calcium Transport along the Male Rat Kidney: Effect of Diuretics

Modeling magnesium and calcium transport along male rat kidney and the effects of diuretics

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

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