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Journal of the American Society of... Mar 2022Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and... (Review)
Review
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
Topics: Acute Kidney Injury; Apoptosis; Female; Humans; Kidney; Kidney Cortex Necrosis; Male; Necrosis; Nephrons; Renal Insufficiency, Chronic
PubMed: 35022311
DOI: 10.1681/ASN.2021101293 -
Nature Reviews. Nephrology Jun 2020Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney... (Review)
Review
Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.
Topics: Cellular Senescence; Chlorides; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Glomerular Filtration Barrier; Glomerular Filtration Rate; Glucose; Humans; Hypertrophy; Inflammation; Kidney Glomerulus; Kidney Tubules; Nephrons; Nitric Oxide; Renal Reabsorption; Sodium; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32152499
DOI: 10.1038/s41581-020-0256-y -
Current Heart Failure Reports Apr 2019Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review... (Review)
Review
PURPOSE OF REVIEW
Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF.
RECENT FINDINGS
The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose. Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.
Topics: Diuretics; Drug Resistance; Heart Failure; Humans; Nephrons; Prognosis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 30762178
DOI: 10.1007/s11897-019-0424-1 -
Nature Biotechnology Nov 2015Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regeneration, disease modeling and drug screening. We report an efficient,...
Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regeneration, disease modeling and drug screening. We report an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2+ SALL1+ WT1+ PAX2+ NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8+ LHX1+ renal vesicles that self-organize into nephron structures. In both two- and three-dimensional culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidney development and toxicity.
Topics: Biomedical Research; Cell Culture Techniques; Cell Differentiation; Humans; Kidney; Models, Biological; Nephrons; Organoids; Pluripotent Stem Cells; Tissue Culture Techniques
PubMed: 26458176
DOI: 10.1038/nbt.3392 -
Nefrologia : Publicacion Oficial de La... 2016Hyperchloremia is a common electrolyte disorder that is associated with a diverse group of clinical conditions. The kidney plays an important role in the regulation of... (Review)
Review
Hyperchloremia is a common electrolyte disorder that is associated with a diverse group of clinical conditions. The kidney plays an important role in the regulation of chloride concentration through a variety of transporters that are present along the nephron. Nevertheless, hyperchloremia can occur when water losses exceed sodium and chloride losses, when the capacity to handle excessive chloride is overwhelmed, or when the serum bicarbonate is low with a concomitant rise in chloride as occurs with a normal anion gap metabolic acidosis or respiratory alkalosis. The varied nature of the underlying causes of the hyperchloremia will, to a large extent, determine how to treat this electrolyte disturbance.
Topics: Acid-Base Equilibrium; Acidosis; Alkalosis, Respiratory; Bicarbonates; Cell Membrane Permeability; Chlorides; Formates; Humans; Ion Transport; Kidney Tubules, Proximal; Membrane Transport Proteins; Natriuresis; Nephrons; Oxalates; Water-Electrolyte Imbalance
PubMed: 27267918
DOI: 10.1016/j.nefro.2016.04.001 -
Developmental Cell Nov 2019Chronic kidney disease affects 10% of the population with notable differences in ethnic and sex-related susceptibility to kidney injury and disease. Kidney dysfunction...
Chronic kidney disease affects 10% of the population with notable differences in ethnic and sex-related susceptibility to kidney injury and disease. Kidney dysfunction leads to significant morbidity and mortality and chronic disease in other organ systems. A mouse-organ-centered understanding underlies rapid progress in human disease modeling and cellular approaches to repair damaged systems. To enhance an understanding of the mammalian kidney, we combined anatomy-guided single-cell RNA sequencing of the adult male and female mouse kidney with in situ expression studies and cell lineage tracing. These studies reveal cell diversity and marked sex differences, distinct organization and cell composition of nephrons dependent on the time of nephron specification, and lineage convergence, in which contiguous functionally related cell types are specified from nephron and collecting system progenitor populations. A searchable database, Kidney Cell Explorer (https://cello.shinyapps.io/kidneycellexplorer/), enables gene-cell relationships to be viewed in the anatomical framework of the kidney.
Topics: Animals; Cell Lineage; Epithelial Cells; Female; Kidney; Male; Mice; Nephrons; Sex Characteristics; Single-Cell Analysis; Time Factors
PubMed: 31689386
DOI: 10.1016/j.devcel.2019.10.005 -
American Journal of Physiology. Renal... May 2019Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration.... (Review)
Review
Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration. Each mechanism generates a self-sustained oscillation, the mechanisms interact, and the oscillations synchronize. The synchronization generates a bimodal electrical signal in the arteriolar wall that propagates retrograde to a vascular node, where it meets similar electrical signals from other nephrons. Each signal carries information about the time-dependent behavior of the regulatory ensemble. The converging signals support synchronization of the nephrons participating in the information exchange, and the synchronization can lead to formation of nephron clusters. We review the experimental evidence and the theoretical implications of these interactions and consider additional interactions that can limit the size of nephron clusters. The architecture of the arterial tree figures prominently in these interactions.
Topics: Animals; Arterioles; Blood Flow Velocity; Glomerular Filtration Rate; Homeostasis; Humans; Kidney Glomerulus; Kidney Tubules; Models, Biological; Renal Circulation; Signal Transduction
PubMed: 30759020
DOI: 10.1152/ajprenal.00484.2018 -
Frontiers in Public Health 2021Early onset hypertension is one of many major medical disorders that have evolved over the current millennium across both the developing as well as the developed world.... (Review)
Review
Early onset hypertension is one of many major medical disorders that have evolved over the current millennium across both the developing as well as the developed world. Though various mechanisms have been postulated for the evolution of hypertension in these individuals, one of the most relevant ones is that of low birth weight and its association with hypertension. Barker from historical evidence has postulated the foetal onset adult disease (FOAD) or Thrifty phenotype on Low Birth Weight (LBW) associated hypertension. Later, Brenner highlighted the importance of low nephron mass and future implications. In this review we elaborate the mechanisms that were postulated for LBW-related hypertension as well the potential antihypertensive therapy that may be used in these individuals.
Topics: Humans; Hypertension; Infant, Low Birth Weight; Infant, Newborn; Nephrons
PubMed: 35127619
DOI: 10.3389/fpubh.2021.767545 -
Advances in Physiology Education Jun 2018The purpose of this study is to see whether a large drawing of a nephron helped medical students in self-directed learning groups learn renal physiology, histology, and...
The purpose of this study is to see whether a large drawing of a nephron helped medical students in self-directed learning groups learn renal physiology, histology, and pharmacology before discussing clinical cases. The end points were the grades on the renal examination and a student survey. The classes in the fall of 2014 and 2015 used the drawing, but not those of 2012 and 2013. The Charles E. Schmidt College of Medicine at Florida Atlantic University is a newly formed Florida medical school, which enrolled its first class in the fall of 2011. The school relies on self-directed problem-based learning in year 1 and changes over to a case inquiry method in the latter part of year 1 and throughout year 2. At the start of the renal course, each student group received a poster of a nephron with the objective of learning the cell functions of the different nephron parts. During the first year of using the drawing, there was no improvement in grades. After a student suggested adjustment to the drawing, there was a statistically significant difference in the total test score in the second year ( P < 0.001). An unexpected finding was lower grades in all 4 yr in the area of acid-base balance and electrolytes compared with the other four areas tested. In the survey, the students found the drawing useful.
Topics: Education, Medical; Educational Measurement; Female; Histology; Humans; Kidney; Male; Nephrons; Pharmacology; Physiology; Problem-Based Learning; Retrospective Studies; Students, Medical; Teaching; Young Adult
PubMed: 29616568
DOI: 10.1152/advan.00022.2017 -
Journal of the American Society of... Jan 2015Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine... (Review)
Review
Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK) proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered.
Topics: Aldosterone; Cations; Claudins; Epithelial Cells; Epithelium; Humans; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Magnesium; Mutation; Nephrons; Permeability; Polymorphism, Genetic; Potassium; Salts; Sodium; Water
PubMed: 24948743
DOI: 10.1681/ASN.2014030284