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Current Heart Failure Reports Apr 2023The lymphatic system plays a major but overlooked role in maintaining fluid homeostasis. Given the unique fluid homeostasis functions of the kidneys, dysregulation of... (Review)
Review
PURPOSE OF REVIEW
The lymphatic system plays a major but overlooked role in maintaining fluid homeostasis. Given the unique fluid homeostasis functions of the kidneys, dysregulation of the renal lymphatic system underlies the development of self-propagating congestive pathomechanisms. In this review, we outline the roles of the renal lymphatic system in heart failure (HF).
RECENT FINDINGS
Studies have uncovered several pathomechanisms involving the renal lymphatic system in congestive states, such as impaired interstitial draining by the renal lymphatic system, impaired structure and valves of renal lymphatics, lymphatic-induced increase in renal reabsorption of water and sodium, and development of albuminuria with proteinuria-induced renal lymphangiogenesis. These self-propagating mechanisms result in "renal tamponade" with manifestations of cardiorenal syndrome and inappropriate renal response to diuretics. Dysregulation of the renal lymphatic system is integral to the development and progression of congestion in HF. Targeting renal lymphatics may provide a novel pathway to treat intractable congestion.
Topics: Humans; Heart Failure; Kidney; Cardio-Renal Syndrome; Lymphatic System; Diuretics
PubMed: 36848025
DOI: 10.1007/s11897-023-00595-0 -
Frontiers in Bioscience (Landmark... Mar 2023Maintaining a balance between the supply and demand of oxygen is vital for proper organ function. Most types of acute kidney injury (AKI) are characterized by hypoxia, a... (Review)
Review
Maintaining a balance between the supply and demand of oxygen is vital for proper organ function. Most types of acute kidney injury (AKI) are characterized by hypoxia, a state where the supply of oxygen cannot match the demand for normal cellular activities. Hypoxia results from hypo perfusion and impaired microcirculation in the kidney. It inhibits mitochondrial oxidative phosphorylation, resulting in a decrease in production of adenosine triphosphate (ATP), which is essential to power tubular transport activities, especially reabsorption of Na+, and other vital cellular activities. To ameliorate AKI, the majority of studies have focused on increasing renal oxygen delivery by restoring renal blood flow and altering intra-renal hemodynamics. However, to date these approaches remain inadequate. In addition to augmenting oxygen supply, increasing renal blood flow also increases glomerular filtration rate, leading to increased solute deliver and workload for the renal tubules, causing an increase in oxygen consumption. The relationship between Na+ reabsorption and oxygen expenditure in the kidney is linear. Experimental models have demonstrated that inhibition of Na+ reabsorption can alleviate AKI. Since the proximal tubules reabsorb approximately 65% of filtered Na+, consuming the largest portion of oxygen, many studies focus on examining the effects of inhibiting Na+ reabsorption in this segment. Potential therapeutics that have been examined include acetazolamide, dopamine and its analog, inhibitors of the renin-angiotensin II system, atrial natriuretic peptide, and empagliflozin. The effectiveness of inhibition of Na+ reabsorption in the thick ascending limb of the Loop of Henle by furosemide has been also examined. While these approaches produced impressive results in animal models, their clinical benefits remain mixed. This review summarizes the progress in this area and argues that the combination of increasing oxygen supply with decreasing oxygen consumption or different approaches to reducing oxygen demand will be more efficacious.
Topics: Animals; Kidney; Acute Kidney Injury; Kidney Tubules, Proximal; Sodium; Oxygen; Hypoxia; Oxygen Consumption
PubMed: 37005768
DOI: 10.31083/j.fbl2803062 -
American Journal of Physiology. Renal... Aug 2017Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral... (Review)
Review
Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral resistance. It is commonly accepted that increased renal sodium handling and plasma volume expansion are necessary factors for the development of salt-induced hypertension. The epithelial sodium channel (ENaC) is a trimeric ion channel expressed in the distal nephron that plays a critical role in the regulation of sodium reabsorption in both normal and pathological conditions. In this mini-review, we summarize recent studies investigating the role of ENaC in the development of salt-sensitive hypertension. On the basis of experimental data obtained from the Dahl salt-sensitive rats, we and others have demonstrated that abnormal ENaC activation in response to a dietary NaCl load contributes to the development of high blood pressure in this model. The role of different humoral factors, such as the components of the renin-angiotensin-aldosterone system, members of the epidermal growth factors family, arginine vasopressin, and oxidative stress mediating the effects of dietary salt on ENaC are discussed in this review to highlight future research directions and to determine potential molecular targets for drug development.
Topics: Animals; Arginine Vasopressin; Blood Pressure; Disease Models, Animal; EGF Family of Proteins; Epithelial Cells; Epithelial Sodium Channels; Humans; Hypertension; Hypoglycemic Agents; Molecular Targeted Therapy; Nephrons; Oxidative Stress; Rats, Inbred Dahl; Renal Reabsorption; Renin-Angiotensin System; Signal Transduction; Sodium Chloride, Dietary
PubMed: 28003189
DOI: 10.1152/ajprenal.00427.2016 -
American Journal of Nephrology 2022In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid... (Review)
Review
BACKGROUND
In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid hormone or vitamin D and was attributed to a direct action of metabolic acidosis on the renal tubular cells. The latter has been verified by recent studies on the molecular levels in the kidney.
SUMMARY
Whereas the regulatory role of urinary calcium excretion was traditionally assigned to the transcellular calcium transport in the distal convoluted tubule (DCT) and connecting tubule (CNT), most of the calcium reabsorption from the glomerular filtrate paracellularly occurs through the tight junctions in the proximal tubule (PT) and the thick ascending limb (TAL) of Henle's loop. Interestingly, all these nephron segments participate in producing hypercalciuria caused by metabolic acidosis. Claudin-2 is the major route of paracellular calcium transport in the PT and was downregulated in rats with 5 days' NH4Cl loading. In the TAL, the lumen-positive voltage produced by apical K+ recycling drives paracellular reabsorption of Ca2+ and Mg2+ via the claudin-16/19 complex. Activation of calcium-sensing receptor (CaSR) by extracellular calcium upregulates claudin-14, which in turn interacts with the claudin-16/19 complex and inhibits its cation permeability. This TAL CaSR-claudins axis was activated by chronic NH4Cl loading in rats. Finally, the major transcellular calcium transporters TRPV5 and 28K calcium-binding protein in the DCT-CNT were also downregulated by NH4Cl or acetazolamide administration in mice.
KEY MESSAGES
Both paracellular and transcellular calcium transport pathways in the kidney are regulated by metabolic acidosis and lead to renal calcium wasting. In the PT, claudin-2 is downregulated by acidic pH. In the TAL of Henle's loop, CaSR is stimulated by the ionized calcium released from bone and upregulates claudin-14, which in turn inhibits the claudin-16/19 complex and leads to calcium and magnesium wasting. Finally, the transcellular calcium transporters, TRPV5 and calbindin-D28K, are downregulated by metabolic acidosis in the DCT and CNT.
Topics: Mice; Rats; Animals; Calcium; Hypercalciuria; Claudin-2; Claudins; Kidney; Acidosis
PubMed: 36450225
DOI: 10.1159/000528089 -
Pflugers Archiv : European Journal of... Mar 2015Dietary potassium (K(+)) intake has antihypertensive effects, prevents strokes, and improves cardiovascular outcomes. The underlying mechanism for these beneficial... (Review)
Review
Dietary potassium (K(+)) intake has antihypertensive effects, prevents strokes, and improves cardiovascular outcomes. The underlying mechanism for these beneficial effects of high K(+) diets may include vasodilation, enhanced urine flow, reduced renal renin release, and negative sodium (Na(+)) balance. Indeed, several studies demonstrate that dietary K(+) intake induces renal Na(+) loss despite elevated plasma aldosterone. This review briefly highlights the epidemiological and experimental evidences for the effects of dietary K(+) on arterial blood pressure. It discusses the pivotal role of the renal distal tubule for the regulation of urinary K(+) and Na(+) excretion and blood pressure and highlights that it depends on the coordinated interaction of different nephron portions, epithelial cell types, and various ion channels, transporters, and ATPases. Moreover, we discuss the relevance of aldosterone and aldosterone-independent factors in mediating the effects of an altered K(+) intake on renal K(+) and Na(+) handling. Particular focus is given to findings suggesting that an aldosterone-independent downregulation of the thiazide-sensitive NaCl cotransporter significantly contributes to the natriuretic and antihypertensive effect of a K(+)-rich diet. Last but not least, we refer to the complex signaling pathways enabling the kidney to adapt its function to the homeostatic needs in response to an altered K(+) intake. Future work will have to further address the underlying cellular and molecular mechanism and to elucidate, among others, how an altered dietary K(+) intake is sensed and how this signal is transmitted to the different epithelial cells lining the distal tubule.
Topics: Animals; Blood Pressure; Humans; Kidney; Potassium, Dietary; Renal Reabsorption; Water-Electrolyte Balance
PubMed: 25559844
DOI: 10.1007/s00424-014-1673-1 -
Nefrologia : Publicacion Oficial de La... 2015Paracellular channels occurring in tight junctions play a major role in transepithelial ionic flows. This pathway includes a high number of proteins, such as claudins.... (Review)
Review
Paracellular channels occurring in tight junctions play a major role in transepithelial ionic flows. This pathway includes a high number of proteins, such as claudins. Within renal epithelium, claudins result in an ionic selectivity in tight junctions. Ascending thick limb of loop of Henle (ATLH) is the most important segment for calcium reabsorption in renal tubules. Its cells create a water-proof barrier, actively transport sodium and chlorine through a transcellular pathway, and provide a paracellular pathway for selective calcium reabsorption. Several studies have led to a model of paracellular channel consisting of various claudins, particularly claudin-16 and 19. Claudin-16 mediates cationic paracellular permeability in ATLH, whereas claudin-19 increases cationic selectivity of claudin-16 by blocking anionic permeability. Recent studies have shown that claudin-14 promoting activity is only located in ATLH. When co-expressed with claudin-16, claudin-14 inhibits the permeability of claudin-16 and reduces paracellular permeability to calcium. Calcium reabsorption process in ATLH is closely regulated by calcium sensor receptor (CaSR), which monitors circulating Ca levels and adjusts renal excretion rate accordingly. Two microRNA, miR-9 and miR-374, are directly regulated by CaSR. Thus, miR-9 and miR-374 suppress mRNA translation for claudin-14 and induce claudin-14 decline.
Topics: Animals; Anions; Biological Transport, Active; Calcium; Cations; Cell Membrane Permeability; Chlorides; Claudins; Humans; Loop of Henle; Mice; Mice, Knockout; MicroRNAs; Protein Biosynthesis; Protein Isoforms; Receptors, Calcium-Sensing; Renal Reabsorption; Sodium; Tight Junctions; Transcytosis
PubMed: 26306950
DOI: 10.1016/j.nefro.2015.06.011 -
Nature Reviews. Nephrology Jun 2020The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine... (Review)
Review
The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine flows through the nephron in a highly dynamic manner and adjustment of the reabsorption rates of water and ions to the variable tubular flow is required for electrolyte homeostasis. Renal epithelial cells sense the tubular flow by mechanosensation. Interest in this phenomenon has increased in the past decade since the acknowledgement of primary cilia as antennae that sense renal tubular flow. However, the significance of tubular flow sensing for electrolyte handling is largely unknown. Signal transduction pathways regulating flow-sensitive physiological responses involve calcium, purinergic and nitric oxide signalling, and are considered to have an important role in renal electrolyte handling. Given that mechanosensation of tubular flow is an integral role of the nephron, defective tubular flow sensing is probably involved in renal disease. Studies investigating tubular flow and electrolyte transport differ in their methodology, subsequently hampering translational validity. This Review provides the basis for understanding electrolyte disorders originating from altered tubular flow sensing as a result of pathological conditions.
Topics: Body Water; Calcium Signaling; Cilia; Electrolytes; Epithelial Cells; Glomerular Filtration Rate; Humans; Kidney Pelvis; Kidney Tubules; Mechanotransduction, Cellular; Microfluidics; Nitric Oxide; Receptors, Purinergic; Renal Reabsorption; Signal Transduction; Water-Electrolyte Balance; Water-Electrolyte Imbalance
PubMed: 32127698
DOI: 10.1038/s41581-020-0259-8 -
Electrolyte & Blood Pressure : E & BP Jun 2021Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of... (Review)
Review
Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of urate removal and has a pivotal role in the regulation of urate homeostasis. Approximately 10% of the glomerular filtered urate is excreted in the urine, and the remainder is reabsorbed by the proximal tubule. However, the transport of urate in the proximal tubule is bidirectional: reabsorption and secretion. Thus, an increase in reabsorption or a decrease in secretion may induce hyperuricemia. In contrast, a decrease in reabsorption or an increase in secretion may result in hyperuricosuria. In the proximal tubule, urate reabsorption is mainly mediated by apical URAT1 () and basolateral GLUT9 () transporter. OAT4 () also acts in urate reabsorption in the apical membrane, and its polymorphism is associated with the risk of hyperuricemia. Renal hypouricemia is caused by or loss-of-function mutations, and it may be complicated by exercise-induced acute kidney injury. URAT1 and GLUT9 are also drug targets for uricosuric agents. Sodium-glucose cotransporter inhibitors may induce hyperuricosuria by inhibiting GLUT9b located in the apical plasma membrane. Urate secretion is mediated by basolateral OAT1 () and OAT3 () and apical ATP-binding cassette super-family G member 2 (), NPT1 (), and NPT4 () transporter in the proximal tubule. NPT1 and NPT4 may be key players in renal urate secretion in humans, and deletion of and in mice leads to decreased urate excretion. Dysfunctional variants of inhibit urate secretion from the gut and kidney and may cause gout. In summary, the net result of urate transport in the proximal tubule is determined by the dominance of transporters between reabsorption (URAT1, OAT4, and GLUT9) and secretion (ABCG2, NPT1, NPT4, OAT1, and OAT3).
PubMed: 34290818
DOI: 10.5049/EBP.2021.19.1.1 -
Current Rheumatology Reports Jun 2016Elevated serum urate concentration is the primary cause of gout. Understanding the processes that affect serum urate concentration is important for understanding the... (Review)
Review
Elevated serum urate concentration is the primary cause of gout. Understanding the processes that affect serum urate concentration is important for understanding the etiology of gout and thereby understanding treatment. Urate handing in the human body is a complex system including three major processes: production, renal elimination, and intestinal elimination. A change in any one of these can affect both the steady-state serum urate concentration as well as other urate processes. The remarkable complexity underlying urate regulation and its maintenance at high levels in humans suggests that this molecule could potentially play an interesting role other than as a mere waste product to be eliminated as rapidly as possible.
Topics: Gout; Humans; Hyperuricemia; Intestinal Mucosa; Kidney; Kidney Tubules; Organic Anion Transporters; Renal Reabsorption; Uric Acid
PubMed: 27105641
DOI: 10.1007/s11926-016-0587-7 -
Comprehensive Physiology Dec 2015Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes.... (Review)
Review
Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function.
Topics: Animals; Apoptosis; Arachidonate Lipoxygenases; Cytochrome P-450 Enzyme System; Hemodynamics; Humans; Kidney; Renal Reabsorption
PubMed: 26756638
DOI: 10.1002/cphy.c150009