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The Journal of Physiology Sep 2014The regulation of extracellular fluid volume by renal sodium excretion lies at the centre of blood pressure homeostasis. Renal perfusion pressure can directly regulate... (Review)
Review
The regulation of extracellular fluid volume by renal sodium excretion lies at the centre of blood pressure homeostasis. Renal perfusion pressure can directly regulate sodium reabsorption in the proximal tubule. This acute pressure natriuresis response is a uniquely powerful means of stabilizing long-term blood pressure around a set point. By logical extension, deviation from the set point can only be sustained if the pressure natriuresis mechanism is impaired, suggesting that hypertension is caused or sustained by a defect in the relationship between renal perfusion pressure and sodium excretion. Here we describe the role of pressure natriuresis in blood pressure control and outline the cascade of biophysical and paracrine events in the renal medulla that integrate the vascular and tubular response to altered perfusion pressure. Pressure natriuresis is impaired in hypertension and mechanistic insight into dysfunction comes from genetic analysis of blood pressure disorders. Transplantation studies in rats show that blood pressure is determined by the genotype of the kidney and Mendelian hypertension indicates that the distal nephron influences the overall natriuretic efficiency. These approaches and the outcomes of genome-wide-association studies broaden our view of blood pressure control, suggesting that renal sympathetic nerve activity and local inflammation can impair pressure natriuresis to cause hypertension. Understanding how these systems interact is necessary to tackle the global burden of hypertension.
Topics: Animals; Blood Pressure; Humans; Hypertension; Kidney; Natriuresis; Sympathetic Nervous System
PubMed: 25107929
DOI: 10.1113/jphysiol.2014.271676 -
American Journal of Physiology. Renal... Sep 2014Renal medullary function is characterized by corticopapillary concentration gradients of various molecules. One example is the generally decreasing axial gradient in... (Review)
Review
Renal medullary function is characterized by corticopapillary concentration gradients of various molecules. One example is the generally decreasing axial gradient in oxygen tension (Po2). Another example, found in animals in the antidiuretic state, is a generally increasing axial solute gradient, consisting mostly of NaCl and urea. This osmolality gradient, which plays a principal role in the urine concentrating mechanism, is generally considered to involve countercurrent multiplication and countercurrent exchange, although the underlying mechanism is not fully understood. Radial oxygen and solute gradients in the transverse dimension of the medullary parenchyma have been hypothesized to occur, although strong experimental evidence in support of these gradients remains lacking. This review considers anatomic features of the renal medulla that may impact the formation and maintenance of oxygen and solute gradients. A better understanding of medullary architecture is essential for more clearly defining the compartment-to-compartment flows taken by fluid and molecules that are important in producing axial and radial gradients. Preferential interactions between nephron and vascular segments provide clues as to how tubular and interstitial oxygen flows contribute to safeguarding active transport pathways in renal function in health and disease.
Topics: Animals; Humans; Kidney Medulla; Microvessels; Oxygen
PubMed: 25056344
DOI: 10.1152/ajprenal.00276.2014 -
Biology of Sex Differences Sep 2020Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential...
BACKGROUND
Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na transport. Activation of these receptors inhibits epithelial Na channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y and P2Y receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y and P2Y) receptors regulating Na excretion compared to male and OVX rats.
METHODS
To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y and P2Y receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E, 0, 10, 100, and 1000 nM) to test whether E increases mRNA expression of P2Y and P2Y receptors.
RESULTS
Acute P2 inhibition attenuated urinary Na excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y and P2Y mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E dose-dependently upregulated P2Y and P2Y mRNA expression in mIMCD3.
CONCLUSION
These data suggest that ovary-intact females have enhanced P2Y and P2Y-dependent regulation of Na handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na handling in premenopausal females.
Topics: Animals; Cell Line; Dose-Response Relationship, Drug; Epithelial Sodium Channels; Estradiol; Female; Gene Expression Regulation; Kidney Medulla; Male; Natriuresis; Ovariectomy; Ovary; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Sex Factors; Suramin; Type C Phospholipases
PubMed: 32928299
DOI: 10.1186/s13293-020-00329-0 -
American Journal of Physiology. Renal... Feb 2020The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with... (Review)
Review
The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with different composition of the peritubular environment. The TAL plays a critical role in the control of NaCl, water, acid, and divalent cation homeostasis, as illustrated by the consequences of the various monogenic diseases that affect the TAL. It delivers tubular fluid to the distal convoluted tubule and thereby affects the function of the downstream tubular segments. The TAL is commonly considered as a whole. However, many structural and functional differences exist between its medullary and cortical parts. The present review summarizes the available data regarding the similarities and differences between the medullary and cortical parts of the TAL. Both subsegments reabsorb NaCl and have high Na-K-ATPase activity and negligible water permeability; however, they express distinct isoforms of the Na-K-2Cl cotransporter at the apical membrane. Ammonia and bicarbonate are mostly reabsorbed in the medullary TAL, whereas Ca and Mg are mostly reabsorbed in the cortical TAL. The peptidic hormone receptors controlling transport in the TAL are not homogeneously expressed along the cortical and medullary TAL. Besides this axial heterogeneity, structural and functional differences are also apparent between species, which underscores the link between properties and role of the TAL under various environments.
Topics: Adaptation, Physiological; Animals; Evolution, Molecular; Humans; Kidney Cortex; Kidney Medulla; Loop of Henle; Membrane Transport Proteins; Renal Reabsorption; Species Specificity; Water-Electrolyte Balance
PubMed: 31841389
DOI: 10.1152/ajprenal.00261.2019 -
Biology Feb 2023Acute kidney injury (AKI) can result from multiple factors. The main cause is reduced renal perfusion. Kidneys are susceptible to ischemia due to the anatomy of... (Review)
Review
Acute kidney injury (AKI) can result from multiple factors. The main cause is reduced renal perfusion. Kidneys are susceptible to ischemia due to the anatomy of microcirculation that wraps around the renal tubules-peritubular capillary (PTC) network. Cortical and medullary superficial tubules have a large share in transport and require the supply of oxygen for ATP production, while it is the cortex that receives almost 100% of the blood flowing through the kidneys and the medulla only accounts for 5-10% of it. This difference makes the tubules present in the superficial layer of the medulla very susceptible to ischemia. Impaired blood flow causes damage to the endothelium, with an increase in its prothrombotic and pro-adhesive properties. This causes congestion in the microcirculation of the renal medulla. The next stage is the migration of pericytes with the disintegration of these vessels. The phenomenon of destruction of small vessels is called peritubular rarefaction, attributed as the main cause of further irreversible changes in the damaged kidney leading to the development of chronic kidney disease. In this article, we will present the characteristic structure of renal microcirculation, its regulation, and the mechanism of damage in acute ischemia, and we will try to find methods of prevention with particular emphasis on the inhibition of the renin-angiotensin-aldosterone system.
PubMed: 36829602
DOI: 10.3390/biology12020327 -
Kidney & Blood Pressure Research 2016Recent studies have indicated that local inflammatory mediators are importantly involved in the regulation of renal function. However, it remains unknown how such local...
BACKGROUND/AIMS
Recent studies have indicated that local inflammatory mediators are importantly involved in the regulation of renal function. However, it remains unknown how such local inflammation is triggered intracellularly in the kidney. The present study was designed to characterize the inflammasome centered by Nlrp3 in the kidney and also test the effect of its activation in the renal medulla.
METHODS AND RESULTS
By immunohistochemistry analysis, we found that inflammasome components, Nlrp3, Asc and caspase-1, were ubiquitously distributed in different kidney areas. The caspase-1 activity and IL-1β production were particularly high in the renal outer medulla compared to other kidney regions. Further confocal microscopy and RT-PCR analysis showed that Nlrp3, Asc and caspase-1 were particularly enriched in the thick ascending limb of Henle's loop. In anesthetized mice, medullary infusion of Nlrp3 inflammasome activator, monosodium urate (MSU), induced significant decreases in sodium excretion and medullary blood flow without changes in mean arterial blood pressure and renal cortical blood flow. Caspase-1 inhibitor, Ac-YVAD-CMK and deletion of Nlrp3 or Asc gene abolished MSU-induced decreases in renal sodium excretion and MBF.
CONCLUSION
Our results indicate that renal medullary Nlrp3 inflammasomes represent a new regulatory mechanism of renal MBF and sodium excretion which may not depend on classical inflammatory response.
Topics: Animals; Blood Flow Velocity; Gene Deletion; Inflammasomes; Kidney Medulla; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 27010539
DOI: 10.1159/000443424 -
Journal of Comparative Physiology. B,... Nov 2018Mammalian kidneys play an essential role in balancing internal water and salt concentrations. When water needs to be conserved, the renal medulla produces concentrated... (Review)
Review
Mammalian kidneys play an essential role in balancing internal water and salt concentrations. When water needs to be conserved, the renal medulla produces concentrated urine. Central to this process of urine concentration is an osmotic gradient that increases from the corticomedullary boundary to the inner medullary tip. How this gradient is generated and maintained has been the subject of study since the 1940s. While it is generally accepted that the outer medulla contributes to the gradient by means of an active process involving countercurrent multiplication, the source of the gradient in the inner medulla is unclear. The last two decades have witnessed advances in our understanding of the urine-concentrating mechanism. Details of medullary architecture and permeability properties of the tubules and vessels suggest that the functional and anatomic relationships of these structures may contribute to the osmotic gradient necessary to concentrate urine. Additionally, we are learning more about the membrane transporters involved and their regulatory mechanisms. The role of medullary architecture and membrane transporters in the mammalian urine-concentrating mechanism are the focus of this review.
Topics: Animals; Humans; Kidney Medulla; Membrane Transport Proteins; Urine
PubMed: 29797052
DOI: 10.1007/s00360-018-1164-3 -
Magnetic Resonance in Medical Sciences... Jul 2022To explore the feasibility of susceptibility-weighted imaging (SWI) for evaluating renal iron overload.
PURPOSE
To explore the feasibility of susceptibility-weighted imaging (SWI) for evaluating renal iron overload.
METHODS
Twenty-eight rabbits were randomly assigned into control (n = 14) and iron (n = 14) group. In the 0th week, the study group was injected with iron dextran. Both groups underwent SWI examination at the 0th, 8th, and 12th week. The signal intensity (SI) of cortex and medulla was assessed. Angle radian value (ARV) calculated with phase image was taken as the quantitative value for cortical and medullary iron deposition. After the 12th week, the left kidneys of rabbits were removed for pathology. The difference in the ARV among three groups was analyzed using Kruskal-Wallis test. The difference of the iron content between two groups was analyzed through independent sample t-test.
RESULTS
In the iron group: at the 12th week, eight rabbits were found to have decreased SI of only cortex, and the other six rabbits had decreased SI of cortex and medulla by the same degree; the ARV of cortex at the 8th and 12th week was significantly higher than that of the 0th week (P < 0.05); the ARV of the six rabbits' medulla at the 12th week was significantly higher than that of the 0th week, 8th week, and the other eight rabbits at the 12th week (P < 0.05); at the 12th week, eight rabbits (iron group) were found to have many irons only deposit in the cortex, and the others were found to have many irons deposit in both cortex and medulla; the iron content of cortex and six rabbits' medulla in the iron group was significantly higher than that of the control (P < 0.05).
CONCLUSION
The ARV of SWI can be used to quantitatively assess the excess iron deposition in the kidneys. Excessive iron deposition mainly occurs in the cortex or medulla and causes their SWI SI to decrease.
Topics: Animals; Iron; Iron Overload; Kidney; Magnetic Resonance Imaging; Pilot Projects; Rabbits
PubMed: 33642470
DOI: 10.2463/mrms.mp.2020-0154 -
JCI Insight Oct 2021The prevailing view is that the ClC-Ka chloride channel (mouse Clc-k1) functions in the thin ascending limb to control urine concentration, whereas the ClC-Kb channel...
The prevailing view is that the ClC-Ka chloride channel (mouse Clc-k1) functions in the thin ascending limb to control urine concentration, whereas the ClC-Kb channel (mouse Clc-k2) functions in the thick ascending limb (TAL) to control salt reabsorption. Mutations of ClC-Kb cause classic Bartter syndrome, characterized by renal salt wasting, with perinatal to adolescent onset. We studied the roles of Clc-k channels in perinatal mouse kidneys using constitutive or inducible kidney-specific gene ablation and 2D and advanced 3D imaging of optically cleared kidneys. We show that Clc-k1 and Clc-k2 were broadly expressed and colocalized in perinatal kidneys. Deletion of Clc-k1 and Clc-k2 revealed that both participated in NKCC2- and NCC-mediated NaCl reabsorption in neonatal kidneys. Embryonic deletion of Clc-k2 caused tubular injury and impaired renal medulla and TAL development. Inducible deletion of Clc-k2 beginning after medulla maturation produced mild salt wasting resulting from reduced NCC activity. Thus, both Clc-k1 and Clc-k2 contributed to salt reabsorption in TAL and distal convoluted tubule (DCT) in neonates, potentially explaining the less-severe phenotypes in classic Bartter syndrome. As opposed to the current understanding that salt wasting in adult patients with Bartter syndrome is due to Clc-k2 deficiency in adult TAL, our results suggest that it originates mainly from defects occurring in the medulla and TAL during development.
Topics: Animals; Anion Transport Proteins; Bartter Syndrome; Chloride Channels; Female; Humans; Kidney Medulla; Mice; Pregnancy
PubMed: 34499620
DOI: 10.1172/jci.insight.151039 -
Scientific Reports Nov 2022Development of the renal medulla continues after birth to form mature renal papilla and obtain urine-concentrating ability. Here, we found that a small GTPase, Rac1,...
Development of the renal medulla continues after birth to form mature renal papilla and obtain urine-concentrating ability. Here, we found that a small GTPase, Rac1, plays a critical role in the postnatal development of renal papilla. Mice with distal tubule-specific deletion of Rac1 reached adulthood but showed polydipsia and polyuria with an impaired ability to concentrate urine. The elongation of renal papilla that occurs in the first weeks after birth was impaired in the Rac1-deficient infants, resulting in shortening and damage of the renal papilla. Moreover, the osmoprotective signaling mediated by nuclear factor of activated T cells 5, which is a key molecule of osmotic response to osmotic stress in renal medulla, was significantly impaired in the kidneys of the Rac1-deficient infants. These results demonstrate that Rac1 plays an important role in the development of renal papilla in the postnatal period, and suggested a potential link between Rac1 and osmotic response.
Topics: Mice; Animals; Kidney Medulla; Kidney; Signal Transduction
PubMed: 36434091
DOI: 10.1038/s41598-022-24462-5