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Organogenesis 2012The mature renal medulla, the inner part of the kidney, consists of the medullary collecting ducts, loops of Henle, vasa recta and the interstitium. The unique spatial... (Review)
Review
The mature renal medulla, the inner part of the kidney, consists of the medullary collecting ducts, loops of Henle, vasa recta and the interstitium. The unique spatial arrangement of these components is essential for the regulation of urine concentration and other specialized kidney functions. Thus, the proper and timely assembly of medulla constituents is a crucial morphogenetic event leading to the formation of a functioning metanephric kidney. Mechanisms that direct renal medulla formation are poorly understood. This review describes the current understanding of the key molecular and cellular mechanisms underlying morphological aspects of medulla formation. Given that hypoplasia of the renal medulla is a common manifestation of congenital obstructive nephropathy and other types of congenital anomalies of the kidney and urinary tract (CAKUT), better understanding of how disruptions in medulla formation are linked to CAKUT will enable improved diagnosis, treatment and prevention of CAKUT and their associated morbidity.
Topics: Animals; Humans; Kidney Medulla; Morphogenesis
PubMed: 22343825
DOI: 10.4161/org.19308 -
Frontiers in Bioscience (Landmark... Jan 2017Prostaglandins (PGs) are important autocrine/paracrine regulators that contribute to sodium balance and blood pressure control. Along the nephron, the highest amount of... (Review)
Review
Prostaglandins (PGs) are important autocrine/paracrine regulators that contribute to sodium balance and blood pressure control. Along the nephron, the highest amount of PGE is found in the distal nephron, an important site for fine-tuning of urinary sodium and water excretion. Cylooxygenase-2 (COX-2) is abundantly expressed in the renal medulla and its expression along with urinary PGE excretion is highly induced by chronic salt loading. Factors involved in high salt-induced COX-2 expression in the renal medulla include the hypertonicity, fluid shear stress (FSS), and hypoxia-inducible factor-1 alpha (HIF-1 alpha). Site-specific inhibition of COX-2 in the renal medulla of Sprague-Dawley rats causes sodium retention and salt-sensitive hypertension. Together, these results support the concept that renal medullary COX-2 functions an important natriuretic mediator that is activated by salt loading and its products promote sodium excretion and contribute to maintenance of sodium balance and blood pressure.
Topics: Animals; Cyclooxygenase 2; Dinoprostone; Humans; Hypertension; Kidney Medulla; Natriuresis; Rats; Signal Transduction; Sodium Chloride, Dietary
PubMed: 27814606
DOI: 10.2741/4476 -
Kidney International Feb 1987Like other regional circulations, the medullary circulation supplies oxygen and other primary substrates to the medulla and removes carbon dioxide and other waste... (Review)
Review
Like other regional circulations, the medullary circulation supplies oxygen and other primary substrates to the medulla and removes carbon dioxide and other waste metabolites. It also acts as a countercurrent exchanger and simultaneously removes water reabsorbed from the renal tubule to preserve mass balance. Our present understanding of how the medulla serves both these functions at the same time is illustrated in Figure 3. Blood leaves the efferent arteriole with an elevated plasma protein concentration as a consequence of glomerular filtration, and flows down descending vasa recta within a vascular bundle. The increased interstitial osmotic-concentration coupled with a finite capillary reflection coefficient for small solutes causes additional water to be extracted so that at the termination of descending vasa recta, the plasma protein concentration exceeds that in the systemic circulation by approximately twofold. Solute, urea more than sodium chloride, also enters descending vasa recta. As blood flows through the interconnecting capillary plexus and up ascending vasa recta, transcapillary oncotic and osmotic pressure differences combine to cause capillary uptake of fluid. There is also simultaneous loss of urea such that the medullary trapping of urea is very effective. Countercurrent exchange of sodium chloride, however, appears to be less efficient and as a consequence, not only water but sodium chloride is removed from the medulla. Antidiuretic hormone reduces medullary blood flow, both directly by its vasoconstrictor (V1-receptor mediated) effect and indirectly by its antidiuretic (V2-receptor mediated) effects. Prostaglandins are able to enhance medullary blood flow by counteracting vasoconstrictive influences.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Body Water; Humans; Kidney Medulla; Microcirculation; Prostaglandins; Sodium Chloride; Vasopressins
PubMed: 3550235
DOI: 10.1038/ki.1987.46 -
BMC Nephrology Apr 2022Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this...
BACKGROUND
Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this matter. We studied renal perfusion after renal ischaemia and reperfusion.
METHODS
Renal perfusion distribution was examined by use of Gadolinium-labeled microspheres (MS) after 2 h (hrs) and 4 h ischaemia of the pig kidney followed by 4 h of reperfusion. Intra-arterial injected MS are trapped in the glomeruli in renal cortex, which means that MS are not present in the medulla under normal physiological conditions.
RESULTS
Visual evaluation after reperfusion demonstrated that MS redistributed from the renal cortex to the medulla in 6 out of 16 pigs (38%) subjected to 4 h ischaemia and in one out of 18 pigs subjected to 2 h ischaemia. Central renal uptake of MS covering the medullary/total renal uptake was significantly higher in kidneys subjected to 4 h ischaemia compared with pigs subjected to 2 h ischaemia (69 ± 5% vs. 63 ± 1%, p < 0.001), and also significantly higher than in the contralateral kidney (69 ± 5% vs. 63 ± 2%, p < 0.001). Analysis of blood and urine demonstrated no presence of radioactivity.
CONCLUSION
The study demonstrated the presence of MS in the renal medulla in response to renal ischaemia and reperfusion suggesting that severe ischaemia and reperfusion of the pig kidney leads to opening of functional shunts bypassing glomeruli.
Topics: Animals; Humans; Ischemia; Kidney; Kidney Medulla; Reperfusion; Reperfusion Injury; Swine
PubMed: 35428270
DOI: 10.1186/s12882-022-02780-0 -
ELife Feb 2023Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and...
Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by -gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that -knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.
Topics: Animals; Mice; Amino Acid Transport Systems, Neutral; Ferroptosis; Kidney; Kidney Medulla; Mechanistic Target of Rapamycin Complex 1
PubMed: 36722887
DOI: 10.7554/eLife.80647 -
American Journal of Physiology.... Nov 2019Human studies of renal hemodynamics and metabolism in obesity are insufficient. We hypothesized that renal perfusion and renal free fatty acid (FFA) uptake are higher in...
Human studies of renal hemodynamics and metabolism in obesity are insufficient. We hypothesized that renal perfusion and renal free fatty acid (FFA) uptake are higher in subjects with morbid obesity compared with lean subjects and that they both decrease after bariatric surgery. Cortical and medullary hemodynamics and metabolism were measured in 23 morbidly obese women and 15 age- and sex-matched nonobese controls by PET scanning of [O]-HO (perfusion) and 14()-[F]fluoro-6-thia-heptadecanoate (FFA uptake). Kidney volume and radiodensity were measured by computed tomography, cardiac output by MRI. Obese subjects were re-studied 6 mo after bariatric surgery. Obese subjects had higher renal volume but lower radiodensity, suggesting accumulation of water and/or lipid. Both cardiac output and estimated glomerular filtration rate (eGFR) were increased by ~25% in the obese. Total renal blood flow was higher in the obese [885 (317) (expressed as median and interquartile range) vs. 749 (300) (expressed as means and SD) ml/min of controls, = 0.049]. In both groups, regional blood perfusion was higher in the cortex than medulla; in either region, FFA uptake was ~50% higher in the obese as a consequence of higher circulating FFA levels. Following weight loss (26 ± 8 kg), total renal blood flow was reduced ( = 0.006). Renal volume, eGFR, cortical and medullary FFA uptake were decreased but not fully normalized. Obesity is associated with renal structural, hemodynamic, and metabolic changes. Six months after bariatric surgery, the hemodynamic changes are reversed and the structural changes are improved. On the contrary, renal FFA uptake remains increased, driven by high substrate availability.
Topics: Adult; Bariatric Surgery; Fatty Acids; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Kidney Cortex; Kidney Medulla; Magnetic Resonance Imaging; Middle Aged; Obesity, Morbid; Renal Circulation; Tomography, X-Ray Computed; Weight Loss
PubMed: 31550182
DOI: 10.1152/ajpendo.00135.2019 -
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 -
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 -
The Journal of Clinical Investigation May 2017It has long been viewed that the maintenance of osmotic balance in response to high salt intake is a passive process that is mediated largely by increased water...
It has long been viewed that the maintenance of osmotic balance in response to high salt intake is a passive process that is mediated largely by increased water consumption to balance the salt load. Two studies in this issue of the JCI challenge this notion and demonstrate that osmotic balance in response to high salt intake involves a complex regulatory process that is influenced by hormone fluctuation, metabolism, food consumption, water intake, and renal salt and water excretion. Rakova et al. report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. Kitada et al. extend upon these findings in mouse models and determined that increased urea and a corresponding increase in urea transporters in the renal medulla as the result of increased protein intake promote the water retention that is needed to achieve osmotic homeostasis. Together, the results of these two studies lay the groundwork for future studies to determine how, in the face of chronic changes in salt intake, humans maintain volume and osmotic homeostasis.
Topics: Animals; Glucocorticoids; Humans; Kidney Medulla; Mice; Mineralocorticoids; Sodium Chloride, Dietary; Urea; Water; Water-Electrolyte Balance
PubMed: 28414294
DOI: 10.1172/JCI94004