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Kidney International Jan 2018We summarize the current understanding of the physiology of the renal handling of potassium (K), and present an integrative view of the renal response to K depletion... (Review)
Review
We summarize the current understanding of the physiology of the renal handling of potassium (K), and present an integrative view of the renal response to K depletion caused by dietary K restriction. This renal response involves contributions from different nephron segments, and aims to diminish the rate of excretion of K as a result of: decreasing the rate of electrogenic (and increasing the rate of electroneutral) reabsorption of sodium in the aldosterone-sensitive distal nephron (ASDN), decreasing the abundance of renal outer medullary K channels in the luminal membrane of principal cells in the ASDN, decreasing the flow rate in the ASDN, and increasing the reabsorption of K in the cortical and medullary collecting ducts. The implications of this physiology for the association between K depletion and hypertension, and K depletion and formation of calcium kidney stones are discussed.
Topics: Adaptation, Physiological; Animals; Humans; Hypertension; Kidney Calculi; Nephrons; Potassium Deficiency; Potassium, Dietary; Renal Elimination; Renal Reabsorption
PubMed: 29102372
DOI: 10.1016/j.kint.2017.08.018 -
Pflugers Archiv : European Journal of... Sep 2020The kidneys filter large amounts of glucose. To prevent the loss of this valuable fuel, the tubular system of the kidney, particularly the proximal tubule, has been... (Review)
Review
The kidneys filter large amounts of glucose. To prevent the loss of this valuable fuel, the tubular system of the kidney, particularly the proximal tubule, has been programmed to reabsorb all filtered glucose. The machinery involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane and the facilitative glucose transporter GLUT2 on the basolateral membrane. The proximal tubule also generates new glucose, particularly in the post-absorptive phase but also to enhance bicarbonate formation and maintain acid-base balance. The glucose reabsorbed or formed by the proximal tubule is primarily taken up into peritubular capillaries and returned to the systemic circulation or provided as an energy source to further distal tubular segments that take up glucose by basolateral GLUT1. Recent studies provided insights on the coordination of renal glucose reabsorption, formation, and usage. Moreover, a better understanding of renal glucose transport in disease states is emerging. This includes the kidney in diabetes mellitus, when renal glucose retention becomes maladaptive and contributes to hyperglycemia. Furthermore, enhanced glucose reabsorption is coupled to sodium retention through the sodium-glucose cotransporter SGLT2, which induces secondary deleterious effects. As a consequence, SGLT2 inhibitors are new anti-hyperglycemic drugs that can protect the kidneys and heart from failing. Recent studies discovered unique roles for SGLT1 with implications in acute kidney injury and glucose sensing at the macula densa. This review discusses established and emerging concepts of renal glucose transport, and outlines the need for a better understanding of renal glucose handling in health and disease.
Topics: Acute Kidney Injury; Animals; Humans; Kidney; Renal Reabsorption; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32144488
DOI: 10.1007/s00424-020-02361-w -
Pflugers Archiv : European Journal of... Aug 2017Megalin (or LRP2) is an endocytic receptor that plays a central role in embryonic development and adult tissue homeostasis. Loss of this receptor in congenital or... (Review)
Review
Megalin (or LRP2) is an endocytic receptor that plays a central role in embryonic development and adult tissue homeostasis. Loss of this receptor in congenital or acquired diseases results in multiple organ dysfunctions, including forebrain malformation (holoprosencephaly) and renal reabsorption defects (renal Fanconi syndrome). Here, we describe current concepts of the mode of receptor action that include co-receptors and a repertoire of different ligands, and we discuss how these interactions govern functional integrity of the kidney and the brain, and cause disease when defective.
Topics: Animals; Brain; Endocytosis; Fanconi Syndrome; Holoprosencephaly; Humans; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Renal Reabsorption
PubMed: 28497274
DOI: 10.1007/s00424-017-1992-0 -
American Journal of Physiology. Cell... Sep 2022Renal blood flow represents >20% of total cardiac output and with this comes the great responsibility of maintaining homeostasis through the intricate regulation of... (Review)
Review
Renal blood flow represents >20% of total cardiac output and with this comes the great responsibility of maintaining homeostasis through the intricate regulation of solute handling. Through the processes of filtration, reabsorption, and secretion, the kidneys ensure that solutes and other small molecules are either returned to circulation, catabolized within renal epithelial cells, or excreted through the process of urination. Although this occurs throughout the renal nephron, one segment is tasked with the bulk of solute reabsorption-the proximal tubule. Among others, the renal proximal tubule is entirely responsible for the reabsorption of glucose, a critical source of energy that fuels the body. In addition, it is the only other site of gluconeogenesis outside of the liver. When these processes go awry, pathophysiological conditions such as diabetes and acidosis result. In this review, we highlight the recent advances made in understanding these processes that occur within the renal proximal tubule. We focus on the physiological mechanisms at play regarding glucose reabsorption and glucose metabolism, emphasize the conditions that occur under diseased states, and explore the emerging class of therapeutics that are responsible for restoring homeostasis.
Topics: Glucose; Homeostasis; Kidney; Kidney Tubules, Proximal; Sugars
PubMed: 35912988
DOI: 10.1152/ajpcell.00225.2022 -
Drugs Dec 2014Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2... (Review)
Review
Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs. This article updates an earlier review of dapagliflozin and focuses on longer-term efficacy and tolerability data (e.g. from extensions of earlier clinical trials), as well as data from studies in special patient populations (e.g. history of cardiovascular disease). Numerous well-designed clinical trials with dapagliflozin, primarily as add-on therapy for 24 weeks (but also as monotherapy or initial combination therapy), have consistently demonstrated reductions in glycosylated haemoglobin, fasting plasma glucose levels and bodyweight. Extensions of these trials show the effects are maintained over longer-term follow-up periods of ≈1-4 years and dapagliflozin is generally well tolerated. Dapagliflozin has a low risk of hypoglycaemia, although the incidence varies depending on background therapy, and genital mycotic infections (particularly in women) are the most common adverse events. Dapagliflozin is not recommended in patients with moderate or severe renal impairment. In view of its unique mechanism of action and now well-established efficacy and tolerability profile, dapagliflozin is a useful treatment option in the management of type 2 diabetes, although its effects on diabetic complications remain to be evaluated.
Topics: Benzhydryl Compounds; Biological Availability; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Renal Elimination; Renal Reabsorption; Sodium-Glucose Transport Proteins; Treatment Outcome
PubMed: 25389049
DOI: 10.1007/s40265-014-0324-3 -
Pediatric Nephrology (Berlin, Germany) Oct 2020Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at... (Review)
Review
Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
Topics: Bartter Syndrome; Chloride Channels; Gitelman Syndrome; Humans; Kidney Tubules, Distal; Loop of Henle; Mutation; Renal Reabsorption; Sodium
PubMed: 31664557
DOI: 10.1007/s00467-019-04371-y -
Physiological Reports Jul 2018Active reabsorption of magnesium (Mg ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg homeostasis. Impaired activity of the Na -Cl...
Active reabsorption of magnesium (Mg ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg homeostasis. Impaired activity of the Na -Cl -cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg balance. To further elucidate the possible interrelationship between NCC activity and renal Mg handling, plasma Mg levels and urinary excretion of sodium (Na ) and Mg were measured in a mouse model of Gordon syndrome. In this model, DCT1-specific expression of a constitutively active mutant form of the NCC-phosphorylating kinase, SPAK (CA-SPAK), increases NCC activity and hydrochlorothiazide (HCTZ)-sensitive Na reabsorption. These mice were normomagnesemic and HCTZ administration comparably reduced plasma Mg levels in CA-SPAK mice and control littermates. As inferred by the initial response to HCTZ, CA-SPAK mice exhibited greater NCC-dependent Na reabsorption together with decreased Mg reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA-SPAK mice exhibited higher urinary Mg excretion, while urinary Na excretion decreased to levels observed in control animals. Surprisingly, CA-SPAK mice had unaltered renal expression of Trpm6, encoding the Mg -permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA-SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na reabsorption. Thus, Mg reabsorption is not coupled to increased thiazide-sensitive Na reabsorption, suggesting a similar process explains normomagnesemia in Gordon syndrome. Further research is required to unravel the molecular underpinnings of this phenomenon and the more pronounced Mg excretion after prolonged HCTZ administration.
Topics: Animals; Arthrogryposis; Cation Transport Proteins; Cleft Palate; Clubfoot; Female; Hand Deformities, Congenital; Hydrochlorothiazide; Kidney; Magnesium; Male; Mice; Protein Serine-Threonine Kinases; Renal Reabsorption; Sodium; Sodium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 3; TRPM Cation Channels
PubMed: 30030908
DOI: 10.14814/phy2.13728 -
Current Opinion in Nephrology and... Sep 2017Paracellular transport across the tight junction is a general mechanism for transepithelial transport of solutes in epithelia, including the renal tubule. However, why... (Review)
Review
PURPOSE OF REVIEW
Paracellular transport across the tight junction is a general mechanism for transepithelial transport of solutes in epithelia, including the renal tubule. However, why paracellular transport evolved, given the existence of a highly versatile system for transcellular transport, is unknown.
RECENT FINDINGS
Recent studies have identified the paracellular channel, claudin-2, that is responsible for paracellular reabsorption of sodium in the proximal renal tubule. Knockout of claudin-2 in mice impairs proximal sodium and fluid reabsorption but is compensated by upregulation of sodium reabsorption in the loop of Henle. This occurs at the expense of increased renal oxygen consumption, hypoxia of the outer medulla and increased susceptibility to ischemic kidney injury.
SUMMARY
Paracellular transport can be viewed as a mechanism to exploit the potential energy in existing electrochemical gradients to drive passive transepithelial transport without consuming additional energy. In this way, it enhances the efficiency of energy utilization by transporting epithelia.
Topics: Animals; Biological Transport; Claudins; Energy Metabolism; Humans; Kidney Tubules, Proximal; Loop of Henle; Oxygen Consumption; Renal Reabsorption; Sodium; Tight Junctions
PubMed: 28617689
DOI: 10.1097/MNH.0000000000000348 -
Drugs Jul 2018Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza) is the first protease inhibitor (PI)-based single-tablet regimen (STR) available for the treatment of adults... (Review)
Review
Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza) is the first protease inhibitor (PI)-based single-tablet regimen (STR) available for the treatment of adults and adolescents (aged ≥ 12 years) with HIV-1 infection. It combines the PI darunavir (which has a high genetic barrier to resistance) with the pharmacokinetic booster cobicistat and the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (tenofovir AF), the latter being associated with less off-target tenofovir exposure than its predecessor tenofovir disoproxil fumarate (tenofovir DF). Over 48 weeks in phase 3 trials, darunavir/cobicistat/emtricitabine/tenofovir AF was noninferior to darunavir/cobicistat plus emtricitabine/tenofovir DF in establishing virological suppression in antiretroviral therapy (ART)-naïve adults and, likewise, was noninferior to an ongoing boosted PI, emtricitabine plus tenofovir DF regimen in preventing virological rebound in virologically-suppressed, ART-experienced adults. Resistance did not emerge to the STR components, with the exception being an emtricitabine resistance-associated mutation (RAM) [M184I/V] in one of seven recipients who experienced virological failure (although M184V was a minority variant at screening in this patient). Darunavir/cobicistat/emtricitabine/tenofovir AF was generally well tolerated, with renal and bone profile improvements but less favourable effects on some lipids versus tenofovir DF-based regimens. Thus, although longer-term and cost-effectiveness data would be beneficial, darunavir/cobicistat/emtricitabine/tenofovir AF is a welcome addition to the STRs available for the treatment of adults and adolescents with HIV-1 infection, being the first to combine the high genetic resistance barrier of darunavir with the renal/bone profile of tenofovir AF, thus expanding the patient population for whom an STR may be suitable.
Topics: Adenine; Alanine; Anti-HIV Agents; Bone Density; Cobicistat; Darunavir; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emtricitabine; Genes, MDR; HIV Infections; HIV-1; Humans; Renal Reabsorption; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome
PubMed: 29915897
DOI: 10.1007/s40265-018-0934-2 -
Advances in Therapy Sep 2016Blood glucose-lowering treatment options generally target insulin action or beta-cell function. In diabetes, expression of the sodium-glucose cotransporter-2 (SGLT2)... (Review)
Review
UNLABELLED
Blood glucose-lowering treatment options generally target insulin action or beta-cell function. In diabetes, expression of the sodium-glucose cotransporter-2 (SGLT2) genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening the hyperglycemic condition. The SGLT2 inhibitors (SGLT2i) are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. The efficacy of SGLT2i is reduced in renal impairment because the ability of glucose-lowering is directly proportional to glomerular filtration rate. On the other hand, ongoing research suggests that SGLT2i may offer potential nephroprotection in diabetes. The SGLT2i have been shown to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and the biochemical progression of chronic kidney disease. Additional mechanisms through which SGLT2i exert nephroprotection may include normalizing blood pressure and uricemia. This review explores this bidirectional relationship of the SGLT2i and the glomerulus. While SGLT2i exhibit reduced efficacy in later stages, they exhibit nephroprotective effects in early stages of renal impairment.
FUNDING
Janssen India (Pharmaceutical division of Johnson & Johnson).
Topics: Diabetes Mellitus; Diabetic Nephropathies; Glucose; Humans; Hypoglycemic Agents; Kidney Glomerulus; Renal Elimination; Renal Reabsorption; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 27423646
DOI: 10.1007/s12325-016-0379-5