Sex and circadian regulation of metabolic demands in the rat kidney: A modeling analysis.

Renal hemodynamics, renal transporter expression levels, and urine excretion exhibit circadian variations. Disruption of these diurnal patterns is associated with the pathophysiology of hypertension and chronic kidney disease. Renal hemodynamics determines oxygen delivery, whereas renal transport and metabolism determines oxygen consumption; the balance between them yields renal oxygenation which also demonstrates 24-h periodicity. Another notable modulator of kidney function is sex, which has impacts on renal hemodynamics and transport function that are regulated by as well as independent of the circadian clock. The goal of this study was to investigate the diurnal and sexual variations in renal oxygen consumption and oxygenation. For this purpose, we developed computational models of rat kidney function that represent sexual dimorphism and circadian variation in renal hemodynamics and transporter activities. Model simulations predicted substantial differences in tubular Na+ transport and oxygen consumption among different nephron segments. We also simulated the effect of loop diuretics, which are used in the treatment of renal hypoxia, on medullary oxygen tension. Our model predicted a significantly higher effect of loop diuretics on medullary oxygenation in female rats compared to male rats and when administered during the active phase.

Paradoxes in magnesium transport in Type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis.

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes is observed in Type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rat to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter pattern, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in Type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.

Fatecode enables cell fate regulator prediction using classification-supervised autoencoder perturbation.

Cell reprogramming, which guides the conversion between cell states, is a promising technology for tissue repair and regeneration, with the ultimate goal of accelerating recovery from diseases or injuries. To accomplish this, regulators must be identified and manipulated to control cell fate. We propose Fatecode, a computational method that predicts cell fate regulators based only on single-cell RNA sequencing (scRNA-seq) data. Fatecode learns a latent representation of the scRNA-seq data using a deep learning-based classification-supervised autoencoder and then performs in silico perturbation experiments on the latent representation to predict genes that, when perturbed, would alter the original cell type distribution to increase or decrease the population size of a cell type of interest. We assessed Fatecode's performance using simulations from a mechanistic gene-regulatory network model and scRNA-seq data mapping blood and brain development of different organisms. Our results suggest that Fatecode can detect known cell fate regulators from single-cell transcriptomics datasets.

Renal calcium and magnesium handling during pregnancy: modeling and analysis.

Pregnancy is associated with elevated demand of most nutrients, with many trace elements and minerals critical for the development of fetus. In particular, calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function, and their deficiency can lead to impaired fetal growth. A key contributor to the homeostasis of these ions is the kidney, which in a pregnant rat undergoes major changes in morphology, hemodynamics, and molecular structure. The goal of this study is to unravel the functional implications of these pregnancy-induced changes in renal handling of Ca2+ and Mg2+, two cations that are essential in a healthy pregnancy. To achieve that goal, we developed computational models of electrolyte and water transport along the nephrons of a rat in mid and late pregnancy. Model simulations reveal a substantial increase in the reabsorption of Mg2+ along the proximal tubules and thick ascending limbs. In contrast, the reabsorption of Ca2+ is increased in the proximal tubules but decreased in the thick ascending limbs, due to the lower transepithelial concentration gradient of Ca2+ along the latter. Despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of Ca2+ and Mg2+ in pregnancy. Furthermore, we conducted simulations of hypocalcemia and hypomagnesemia. We found that hypocalcemia lowers Ca2+ excretion substantially more than Mg2+ excretion, with this effect being more pronounced in virgin rats than in pregnant ones. Conversely, hypomagnesemia reduces the excretion of Mg2+ and Ca2+ to more similar degrees. These differences can be explained by the greater sensitivity of the calcium-sensing receptor (CaSR) to Ca2+ compared with Mg2+.NEW & NOTEWORTHY A growing fetus' demands of minerals, notably calcium and magnesium, necessitate adaptations in pregnancy. In particular, the kidney undergoes major changes in morphology, hemodynamics, and molecular structure. This computational modeling study provides insights into how these pregnancy-induced renal adaptation impact calcium and magnesium transport along different nephron segments. Model simulations indicate that, despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of calcium and magnesium in pregnancy.

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

Potassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, and 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 these 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 investigate how these renal alterations impact whole body K+ regulation. Model predictions quantify the sensitivity of K+ regulation to various levels of proximal tubule K+ reabsorption adaptation and tubuloglomerular feedback. 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.NEW & NOTEWORTHY Potassium homeostasis is maintained in the body by a complex system of regulatory mechanisms. This system, when healthy, maintains a small extracellular potassium concentration, despite large fluctuations of dietary potassium. The complexities of the system make this problem well suited for investigation with mathematical modeling. In this study, we extend our mathematical model to consider recent experimental results on renal potassium handling on a high potassium diet and investigate the impacts from a whole body perspective.

How the kidney regulates magnesium: a modelling study.

The kidneys are crucial for maintaining Mg2+ homeostasis. Along the proximal tubule and thick ascending limb, Mg2+ is reabsorbed paracellularly, while along the distal convoluted tubule (DCT), Mg2+ is reabsorbed transcellularly via transient receptor potential melastatin 6 (TRPM6). TRPM6 and other renal transporter expressions are regulated by sex hormones. To investigate renal Mg2 handling, we have developed sex-specific computational models of electrolyte transport along rat superficial nephron. Model simulations indicated that along the proximal tubule and thick ascending limb, Mg2+ and Na+ transport occur parallelly, but they are dissociated along the DCT. In addition, our models predicted higher paracellular Mg2+ permeability in females to attain similar cortical thick ascending limb fractional Mg2+ reabsorption in both sexes. Furthermore, DCT fractional Mg2+ reabsorption is higher in females than in males, allowing females to better fine-tune Mg2+ excretion. We validated our models by simulating the administration of three classes of diuretics. The model predicted significantly increased, marginally increased and significantly decreased Mg2+ excretions for loop, thiazide and K-sparing diuretics, respectively, aligning with experimental findings. The models can be used to conduct in silico studies on kidney adaptations to Mg2+ homeostasis alterations during conditions such as pregnancy, diabetes and chronic kidney disease.

Human Factor Health Data Interoperability.

Comprehensive health data interoperability is recognized as an essential element of high-functioning and accountable health service. Canada is lagging in health data interoperability compared to international comparators, and lacks a comprehensive approach to human factor interoperability, defined as system-level relationships that impact the capacity of health sector stakeholders to adopt harmonized health data standards and technology. Without addressing these system-level relationships, the adoption of harmonized health data standards and technology will be obstructed and Canadians will be underserved. The proposed health data interoperability framework articulates the factors that Canada needs to address to optimize health data design to support quality health programs and services.

Predicting sex differences in the effects of diuretics in renal epithelial transport during angiotensin II-induced hypertension.

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, 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. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, 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 in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.

AI, Machine Learning, and ChatGPT in Hypertension.

Hypertension, a leading cause of cardiovascular disease and premature death, remains incompletely understood despite extensive research. Indeed, even though numerous drugs are available, achieving adequate blood pressure control remains a challenge, prompting recent interest in artificial intelligence. To promote the use of machine learning in cardiovascular medicine, this review provides a brief introduction to machine learning and reviews its notable applications in hypertension management and research, such as disease diagnosis and prognosis, treatment decisions, and omics data analysis. The challenges and limitations associated with data-driven predictive techniques are also discussed. The goal of this review is to raise awareness and encourage the hypertension research community to consider machine learning as a key component in developing innovative diagnostic and therapeutic tools for hypertension. By integrating traditional cardiovascular risk factors with genomics, socioeconomic, behavioral, and environmental factors, machine learning may aid in the development of precise risk prediction models and personalized treatment approaches for patients with hypertension.

Sexual Dimorphism in Substrate Metabolism During Exercise.

During aerobic exercise, women oxidize significantly more lipids and less carbohydrates than men. This sexual dimorphism in substrate metabolism has been attributed, in part, to the observed differences in epinephrine and glucagon levels between men and women during exercise. To identify the underpinning candidate physiological mechanisms for these sex differences, we developed a sex-specific multi-scale mathematical model that relates cellular metabolism in the organs to whole-body responses during exercise. We conducted simulations to test the hypothesis that sex differences in the exercise-induced changes to epinephrine and glucagon would result in the sexual dimorphism of hepatic metabolic flux rates via the glucagon-to-insulin ratio (GIR). Indeed, model simulations indicate that the shift towards lipid metabolism in the female model is primarily driven by the liver. The female model liver exhibits resistance to GIR-mediated glycogenolysis, which helps maintain hepatic glycogen levels. This decreases arterial glucose levels and promotes the oxidation of free fatty acids. Furthermore, in the female model, skeletal muscle relies on plasma free fatty acids as the primary fuel source, rather than intramyocellular lipids, whereas the opposite holds true for the male model.

Sex differences in renal transporters: assessment and functional consequences.

Mammalian kidneys are specialized to maintain fluid and electrolyte homeostasis. The epithelial transport processes along the renal tubule that match output to input have long been the subject of experimental and theoretical study. However, emerging data have identified a new dimension of investigation: sex. Like most tissues, the structure and function of the kidney is regulated by sex hormones and chromosomes. Available data demonstrate sex differences in the abundance of kidney solute and electrolyte transporters, establishing that renal tubular organization and operation are distinctly different in females and males. Newer studies have provided insights into the physiological consequences of these sex differences. Computational simulations predict that sex differences in transporter abundance are likely driven to optimize reproduction, enabling adaptive responses to the nutritional requirements of serial pregnancies and lactation - normal life-cycle changes that challenge the ability of renal transporters to maintain fluid and electrolyte homeostasis. Later in life, females may also undergo menopause, which is associated with changes in disease risk. Although numerous knowledge gaps remain, ongoing studies will provide further insights into the sex-specific mechanisms of sodium, potassium, acid-base and volume physiology throughout the life cycle, which may lead to therapeutic opportunities.

A comparative modeling study of the mitochondrial function of the proximal tubule and thick ascending limb cells in the rat kidney.

To reabsorb >99% of the glomerular filtrate, the metabolic demand of the kidney is high. Interestingly, renal blood flow distribution exhibits marked inhomogeneity, with typical tissue oxygen tension (Po2) of 50-60 mmHg in the well-perfused cortex and 10-20 mmHg in the inner medulla. Cellular fluid composition and acidity also varies substantially. To understand how different renal epithelial cells adapt to their local environment, we have developed and applied computational models of mitochondrial function of proximal convoluted tubule cell (baseline Po2 = 50 mmHg, cytoplasmic pH = 7.20) and medullary thick ascending limb (mTAL) cell (baseline Po2 = 10 mmHg, cytoplasmic pH = 6.85). The models predict key cellular quantities, including ATP generation, P/O (phosphate/oxygen) ratio, proton motive force, electrical potential gradient, oxygen consumption, the redox state of key electron carriers, and ATP consumption. Model simulations predict that close to their respective baseline conditions, the proximal tubule and mTAL mitochondria exhibit qualitatively similar behaviors. Nonetheless, because the mTAL mitochondrion has adapted to a much lower Po2, it can sustain a sufficiently high ATP production at Po2 as low as 4-5 mmHg, whereas the proximal tubule mitochondria would not. Also, because the mTAL cytosol is already acidic under baseline conditions, the proton motive force (pmf) exhibits higher sensitivity to further acidification. Among the different pathways that lead to oxidative phosphorylation impairment, the models predict that both the proximal tubule and mTAL mitochondria are most sensitive to reductions in Complex III activity.NEW & NOTEWORTHY Tissue fluid composition varies substantially within the mammalian kidney. The renal cortex is well perfused and pH neutral, whereas some medullary regions are hypoxic and acidic. How do these environments affect the mitochondrial function of proximal convoluted tubule and medullary thick ascending limb cells, which reside in the cortex and medulla, respectively? This computational modeling study demonstrates that these mitochondria can adapt to their contrasting environments and exhibit different sensitivities to perturbations to local environments.

Adversarial training improves model interpretability in single-cell RNA-seq analysis.

Motivation: Predictive computational models must be accurate, robust, and interpretable to be considered reliable in important areas such as biology and medicine. A sufficiently robust model should not have its output affected significantly by a slight change in the input. Also, these models should be able to explain how a decision is made to support user trust in the results. Efforts have been made to improve the robustness and interpretability of predictive computational models independently; however, the interaction of robustness and interpretability is poorly understood. Results: As an example task, we explore the computational prediction of cell type based on single-cell RNA-seq data and show that it can be made more robust by adversarially training a deep learning model. Surprisingly, we find this also leads to improved model interpretability, as measured by identifying genes important for classification using a range of standard interpretability methods. Our results suggest that adversarial training may be generally useful to improve deep learning robustness and interpretability and that it should be evaluated on a range of tasks. Availability and implementation: Our Python implementation of all analysis in this publication can be found at: https://github.com/MehrshadSD/robustness-interpretability. The analysis was conducted using numPy 0.2.5, pandas 2.0.3, scanpy 1.9.3, tensorflow 2.10.0, matplotlib 3.7.1, seaborn 0.12.2, sklearn 1.1.1, shap 0.42.0, lime 0.2.0.1, matplotlib_venn 0.11.9.

"Hi, how can i help you?": embracing artificial intelligence in kidney research.

In recent years, biology and precision medicine have benefited from major advancements in generating large-scale molecular and biomedical datasets and in analyzing those data using advanced machine learning algorithms. Machine learning applications in kidney physiology and pathophysiology include segmenting kidney structures from imaging data and predicting conditions like acute kidney injury or chronic kidney disease using electronic health records. Despite the potential of machine learning to revolutionize nephrology by providing innovative diagnostic and therapeutic tools, its adoption in kidney research has been slower than in other organ systems. Several factors contribute to this underutilization. The complexity of the kidney as an organ, with intricate physiology and specialized cell populations, makes it challenging to extrapolate bulk omics data to specific processes. In addition, kidney diseases often present with overlapping manifestations and morphological changes, making diagnosis and treatment complex. Moreover, kidney diseases receive less funding compared with other pathologies, leading to lower awareness and limited public-private partnerships. To promote the use of machine learning in kidney research, this review provides an introduction to machine learning and reviews its notable applications in renal research, such as morphological analysis, omics data examination, and disease diagnosis and prognosis. Challenges and limitations associated with data-driven predictive techniques are also discussed. The goal of this review is to raise awareness and encourage the kidney research community to embrace machine learning as a powerful tool that can drive advancements in understanding kidney diseases and improving patient care.

Loss of Glomerular Permselectivity in Type 2 Diabetes Associates With Progression to Kidney Failure.

We examined whether defects in glomerular size selectivity in type 2 diabetes are associated with progressive kidney disease. Glomerular filtration rate (GFR) and fractional clearances of dextrans of graded sizes were measured in 185 American Indians. The permselectivity model that best fit the dextran sieving data represented the glomerular capillary as being perforated by small restrictive pores and a parallel population of larger nonrestrictive pores characterized by ω0, the fraction of total filtrate volume passing through this shunt. The hazard ratio (HR) for kidney failure was expressed per 1-SD increase of ω0 by Cox regression after adjusting for age, sex, mean arterial pressure, HbA1c, GFR, and the urine albumin-to-creatinine ratio (ACR). Baseline mean ± SD age was 43 ± 10 years, HbA1c 8.9 ± 2.5%, GFR 147 ± 46 mL/min, and median (interquartile range) ACR 41 (11-230) mg/g. During a median follow-up of 17.7 years, 67 participants developed kidney failure. After adjustment, each 1-SD increment in ω0 was associated with a higher risk of kidney failure (HR 1.55 [95% CI 1.17, 2.05]). Enhanced transglomerular passage of test macromolecules was associated with progression to kidney failure, independent of albuminuria and GFR, suggesting that mechanisms associated with impaired glomerular permselectivity are important determinants of progressive kidney disease.

Coupling of renal sodium and calcium transport: a modeling analysis of transporter inhibition and sex differences.

Ca2+ transport along the nephron occurs via specific transcellular and paracellular pathways and is coupled to the transport of other electrolytes. Notably, Na+ transport establishes an electrochemical gradient to drive Ca2+ reabsorption. Hence, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na+ transport but also indirectly affect renal Ca2+ handling. To better understand the underlying mechanisms, we developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca2+ handling are represented. Model simulations predicted in the female rat nephron lower Ca2+ reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared with the male nephron. The male rat kidney model yielded a higher urinary Ca2+ excretion than the female model, consistent with animal experiments. Model results indicated that along the proximal tubule and thick ascending limb, Ca2+ and Na+ transport occurred in parallel, but those processes were dissociated in the distal convoluted tubule. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na+ and Ca2+ transport. Simulation results revealed alterations in transepithelial Ca2+ transport, with differential effects among nephron segments and between the sexes.NEW & NOTEWORTHY The kidney plays an important role in the maintenance of whole body Ca2+ balance by regulating Ca2+ reabsorption and excretion. This computational modeling study provides insights into how Ca2+ transport along the nephron is coupled to Na+. Model results indicated that along the proximal tubule and thick ascending limb, Ca2+ and Na+ transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.

Mathematical modeling of calcium homeostasis in female rats: An analysis of sex differences and maternal adaptations.

Calcium plays a vital role in various biological processes, including muscle contractions, blood clotting, skeletal mineralization, and cell signaling. While extracellular calcium makes up less than 1% of total body calcium, it is tightly regulated since too high or too low extracellular calcium concentration can have dangerous effects on the body. Mathematical modeling is a well-suited approach to investigate the complex physiological processes involved in calcium regulation. While mathematical models have been developed to study calcium homeostasis in male rats, none have been used to investigate known sex differences in hormone levels nor the unique physiological states of pregnancy and lactation. Calcitriol, the active form of vitamin D, plays a key role in intestinal calcium absorption, renal calcium reabsorption, and bone remodeling. It has been shown that, when compared to age-matched male rats, females have significantly lower calcitriol levels. In this study we first seek to investigate the impact of this difference as well as other known sex differences on calcium homeostasis using mathematical modeling. Female bodies differ from male bodies in that during their lifetime they may undergo massive adaptations during pregnancy and lactation. Indeed, maternal adaptations impact calcium regulation in all mammals. In pregnant rodents, intestinal absorption of calcium is massively increased in the mother's body to meet the needs of the developing fetus. In a lactating rodent, much of the calcium needs of milk are met by bone resorption, intestinal absorption, and renal calcium reabsorption. Given these observations, the goal of this project is to develop multi-scale whole-body models of calcium homeostasis that represents (1) how sex differences impact calcium homeostasis in female vs. male rats and (2) how a female body adapts to support the excess demands brought on by pregnancy and lactation. We used these models to quantify the impact of individual sex differences as well as maternal adaptations during pregnancy and lactation. Additionally, we conducted "what if" simulations to test whether sex differences in calcium regulation may enable females to better undergo maternal adaptations required in pregnancy and lactation than males.

Sex differences in renal electrolyte transport.

PURPOSE OF REVIEW: Women experience unique life events, for example, pregnancy and lactation, that challenge renal regulation of electrolyte homeostasis. Recent analyses of nephron organization in female vs. male rodent kidneys, revealed distinct sexual dimorphisms in electrolyte transporter expression, abundance, and activity. This review aims to provide an overview of electrolyte transporters' organization and operation in female compared with the commonly studied male kidney, and the (patho)physiologic consequences of the differences. RECENT FINDINGS: When electrolyte transporters are assessed in kidney protein homogenates from both sexes, relative transporter abundance ratios in females/males are less than one along proximal tubule and greater than one post macula densa, which is indicative of a 'downstream shift' in fractional reabsorption of electrolytes in females. This arrangement improves the excretion of a sodium load, challenges potassium homeostasis, and is consistent with the lower blood pressure and greater pressure natriuresis observed in premenopausal women. SUMMARY: We summarize recently reported new knowledge about sex differences in renal transporters: abundance and expression along nephron, implications for regulation by Na + , K + and angiotensin II, and mathematical models of female nephron function.

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

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.