Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron

Tabibzadeh, Nahid; Crambert, Gilles

doi:10.1111/joim.13552

Cited by 15 publications

(14 citation statements)

References 154 publications

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“…Interestingly, imatinib is known to inhibit creatinine tubular secretion [57], suggesting an inhibition of the proximal tubular creatinine transporters, which are also cisplatin transporters [58]. In addition, cisplatin elicits kidney toxicity by penetrating the proximal tubular epithelial cells, subsequently accumulating within these cells and inducing DNA damage [11,12]. Interestingly, Imatinib promotes DNA repair in irradiation-induced cellular damage [59], consistently with our findings, strengthening the view of direct cellular protection by this drug.…”

Section: Discussionsupporting

confidence: 88%

“…For instance, kidney organoids derived from human pluripotent stem cells mimic the intricate complexity of the kidney comprising various cell types, each possessing unique functions and characteristics [7][8][9]. The nephron, which serves as the functional unit of the kidney, assembles into segmented structures composed of podocytes and tubular epithelia, supported by interstitial stromal cells and endothelia [10,11]. These diverse cell types within the kidney interact with each other in complex ways, playing pivotal roles in various pathophysiological processes [12].…”

Section: Introductionmentioning

confidence: 99%

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Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

Oishi,

Tabibzadeh,

Morizane

2024

Biofabrication

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High-throughput drug screening is crucial for advancing healthcare through drug discovery. However, a significant limitation arises from available in vitro models using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in 3D tissues. Recent advancements in stem cell biology have facilitated the generation of organoids—3D tissue constructs that mimic human organs in vitro. Kidney organoids, derived from human pluripotent stem cells, represent a significant breakthrough in disease representation. They encompass major kidney cell types organized within distinct nephron segments, surrounded by stroma and endothelial cells. This tissue allows for the assessment of structural alterations such as nephron loss, a characteristic of chronic kidney disease. Despite these advantages, the complexity of 3D structures has hindered the use of organoids for large-scale drug screening, and the drug screening pipelines utilizing these complex in vitro models are yet to be established for high-throughput screening. In this study, we address the technical limitations of kidney organoids through fully automated 3D imaging, aided by a machine-learning approach for automatic profiling of nephron segment-specific epithelial morphometry. Kidney organoids were exposed to the nephrotoxic agent cisplatin to model severe acute kidney injury. An FDA-approved drug library was tested for therapeutic and nephrotoxicity screening. The fully automated pipeline of 3D image acquisition and analysis identified nephrotoxic or therapeutic drugs during cisplatin chemotherapy. The nephrotoxic potential of these drugs aligned with previous in vivo and human reports. Additionally, Imatinib, a tyrosine kinase inhibitor used in hematological malignancies, was identified as a potential preventive therapy for cisplatin-induced kidney injury. Our proof-of-concept report demonstrates that the automated screening process, using 3D morphometric assays with kidney organoids, enables high-throughput screening for nephrotoxicity and therapeutic assessment in 3D tissue constructs.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

Oishi,

Tabibzadeh,

Morizane

2024

Biofabrication

Self Cite

View full text Add to dashboard Cite

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“…This could lead to excess K + reabsorption, especially in MP where K + retention does not occur normally [ 26 , 28 ]. Excess K + reabsorption without other balancing mechanisms would lead to hyperkalemia [ 22 , 23 , 25 ]. The model predictions presented in this study together with the experimental results from West et al [ 41 ] emphasize the importance of the ENaC during pregnancy for both Na + and K + handling.…”

Section: Discussionmentioning

confidence: 99%

“…The kidneys play an essential role in regulating body homeostasis, namely water, electrolyte, and acid-base balance [22][23][24][25]. During pregnancy, the plasma volume of the mother must expand drastically to support the rapidly developing fetus and placenta [3].…”

Section: Introductionmentioning

confidence: 99%

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

Stadt

West

2023

PLoS ONE

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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.

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“…However, this westernized diet accumulates challenges, such as acidosis resulting from consumption of acid‐producing foods, which can compound and contribute to an elevation in GDF15. K + depletion can also have renal origin, 45 for example, in tubulopathies such as Bartter or Gitelman syndrome or their “pharmacological” equivalent, excess of furosemide or thiazide. In these contexts, we do not know yet whether GDF15 production is stimulated or whether the cell composition of collecting duct is modified.…”

Section: Discussionmentioning

confidence: 99%

GDF15 mediates renal cell plasticity in response to potassium depletion in mice

Lasaad,

Walter,

Rafael

et al. 2023

Acta Physiologica

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ObjectiveTo understand the mechanisms involved in the response to a low‐K+ diet (LK), we investigated the role of the growth factor GDF15 and the ion pump H,K‐ATPase type 2 (HKA2) in this process.MethodsMale mice of different genotypes (WT, GDF15‐KO, and HKA2‐KO) were fed an LK diet for different periods of time. We analyzed GDF15 levels, metabolic and physiological parameters, and the cellular composition of collecting ducts.ResultsMice fed an LK diet showed a 2–4‐fold increase in plasma and urine GDF15 levels. Compared to WT mice, GDF15‐KO mice rapidly developed hypokalemia due to impaired renal adaptation. This is related to their 1/ inability to increase the number of type A intercalated cells (AIC) and 2/ absence of upregulation of H,K‐ATPase type 2 (HKA2), the two processes responsible for K+ retention. Interestingly, we showed that the GDF15‐mediated proliferative effect on AIC was dependent on the ErbB2 receptor and required the presence of HKA2. Finally, renal leakage of K+ induced a reduction in muscle mass in GDF15‐KO mice fed LK diet.ConclusionsIn this study, we showed that GDF15 and HKA2 are linked and play a central role in the response to K+ restriction by orchestrating the modification of the cellular composition of the collecting duct.

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Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron

Abstract: Tabibzadeh N, Crambert G. Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron.

Cited by 15 publications

References 154 publications

Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

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

GDF15 mediates renal cell plasticity in response to potassium depletion in mice

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