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Pediatric Nephrology (Berlin, Germany) Oct 2020Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia... (Review)
Review
Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.
Topics: Absorptiometry, Photon; Bone Development; Bone and Bones; Calcification, Physiologic; Calcitriol; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Osteocytes; Osteomalacia; PHEX Phosphate Regulating Neutral Endopeptidase; Paracrine Communication; Phosphates; Renal Reabsorption; Tooth; Treatment Outcome
PubMed: 31392510
DOI: 10.1007/s00467-019-04290-y -
European Journal of Pharmacology Nov 2018Sodium Glucose Cotransporters 1 (SGLT1) play important roles in the intestinal absorption of glucose and the renal reabsorption of glucose, especially in patients with... (Review)
Review
Sodium Glucose Cotransporters 1 (SGLT1) play important roles in the intestinal absorption of glucose and the renal reabsorption of glucose, especially in patients with uncontrolled diabetes and those receiving SGLT2 inhibitors. As a consequence, the inhibition of SGLT1 transporters may represent an interesting therapeutic option in patients with diabetes. However, genetic models of SGLT1 inactivation indicate that the malfunction of these transporters may have adverse effects on various tissues. In this review, we discuss the available evidence on the beneficial and detrimental effects that the inhibition of SGLT1 transporters might have. The inhibition of SGLT1 lowers serum glucose levels through the inhibition of intestinal absorption and renal reabsorption of glucose. In addition, drugs that interfere with SGLT1-mediated transport of glucose may protect cardiac tissue by reducing glycogen accumulation and decreasing the production of reactive oxygen species. On the other hand, this strategy may result in diarrhea, volume depletion, may interfere with the correction of hypoglycemia through the oral administration of carbohydrates and could predispose to the development of euglycemic diabetic ketoacidosis. Therefore, at the moment, SGLT1 inhibition seems to represent a two-edged sword.
Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetic Ketoacidosis; Diarrhea; Glucose; Humans; Intestinal Absorption; Renal Reabsorption; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome
PubMed: 30240793
DOI: 10.1016/j.ejphar.2018.09.019 -
Nature Communications Jun 2023Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice,...
Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans.
Topics: Humans; Mice; Animals; Nucleosides; Membrane Transport Proteins; Pyrimidine Nucleosides; Renal Elimination; Carrier Proteins; Antimetabolites; Nucleoside Transport Proteins; Kidney
PubMed: 37264059
DOI: 10.1038/s41467-023-38789-8 -
Journal of the American Society of... Sep 2021Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a... (Review)
Review
Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a central role in maintaining serum magnesium within a narrow range (0.70-1.10 mmol/L). Along the proximal tubule and thick ascending limb, magnesium reabsorption occurs via paracellular pathways. Members of the claudin family form the magnesium pores in these segments, and also regulate magnesium reabsorption by adjusting the transepithelial voltage that drives it. Along the distal convoluted tubule transcellular reabsorption via heteromeric TRPM6/7 channels predominates, although paracellular reabsorption may also occur. In this segment, the NaCl cotransporter plays a critical role in determining transcellular magnesium reabsorption. Although the general machinery involved in renal magnesium reabsorption has been identified by studying genetic forms of magnesium imbalance, the mechanisms regulating it are poorly understood. This review discusses pathways of renal magnesium reabsorption by different segments of the nephron, emphasizing newer findings that provide insight into regulatory process, and outlining critical unanswered questions.
Topics: Claudins; Humans; Magnesium; Nephrons; Protein Serine-Threonine Kinases; Renal Reabsorption; TRPM Cation Channels
PubMed: 34045316
DOI: 10.1681/ASN.2021010042 -
Experimental Biology and Medicine... Apr 2017Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through... (Review)
Review
Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through childhood and adolescence until peek mineral density is reached in early adulthood. Thereafter, bone mineral density remains static until it eventually declines in later life. A positive calcium balance, i.e. more calcium absorbed than excreted, is crucial to bone deposition during growth and thus to peek bone mineral density. Dietary calcium is absorbed from the intestine into the blood. It is then filtered by the renal glomerulus and either reabsorbed by the tubule or excreted in the urine. Calcium can be (re)absorbed across intestinal and renal epithelia via both transcellular and paracellular pathways. Current evidence suggests that significant intestinal and renal calcium transport changes occur throughout development. However, the molecular details of these alterations are incompletely delineated. Here we first briefly review the current model of calcium transport in the intestine and renal tubule in the adult. Then, we describe what is known with regard to calcium handling through postnatal development, and how alterations may aid in mediating a positive calcium balance. The role of transcellular and paracellular calcium transport pathways and the contribution of specific intestinal and tubular segments vary with age. However, the current literature highlights knowledge gaps in how specifically intestinal and renal calcium (re)absorption occurs early in postnatal development. Future research should clarify the specific changes in calcium transport throughout early postnatal development including mediators of these alterations enabling appropriate bone mineralization. Impact statement This mini review outlines the current state of knowledge pertaining to the molecules and mechanisms maintaining a positive calcium balance throughout postnatal development. This process is essential to achieving optimal bone mineral density in early adulthood, thereby lowering the lifetime risk of osteoporosis.
Topics: Age Factors; Animals; Biological Transport; Bone Density; Calcium, Dietary; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Kidney Tubules
PubMed: 28346014
DOI: 10.1177/1535370217699536 -
International Journal of Molecular... Dec 2019The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation,... (Review)
Review
The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation, electrolyte-free water reabsorption, and acid-base homeostasis. The collecting duct epithelium is comprised of a tight epithelial barrier resulting in a strict separation of intraluminal urine and the interstitium. Tight junctions are key players in enforcing this barrier and in regulating paracellular transport of solutes across the epithelium. The features of tight junctions across different epithelia are strongly determined by their molecular composition. Claudins are particularly important structural components of tight junctions because they confer barrier and transport properties. In the collecting duct, a specific set of claudins (Cldn-3, Cldn-4, Cldn-7, Cldn-8) is expressed, and each of these claudins has been implicated in mediating aspects of the specific properties of its tight junction. The functional disruption of individual claudins or of the overall barrier function results in defects of blood pressure and water homeostasis. In this concise review, we provide an overview of the current knowledge on the role of the collecting duct epithelial barrier and of claudins in collecting duct function and pathophysiology.
Topics: Animals; Claudins; Epithelial Cells; Humans; Ion Transport; Kidney Tubules, Collecting; Renal Reabsorption
PubMed: 31905642
DOI: 10.3390/ijms21010221 -
Frontiers in Cardiovascular Medicine 2022A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2... (Review)
Review
A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors might be effective alone or in combination with any other drugs. This therapeutic class currently includes five agents: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. SGLT2 inhibitors prevent the renal reabsorption of filtered glucose and sodium by blocking the SGLT2 co-transporters in the proximal convoluted renal tubule, facilitating glucose excretion in the urine (glycosuria) and lowering blood glucose levels. SGLT2 inhibitors have also shown to have pleiotropic effects and determine cardiovascular and renal prevention, thus leading to an extension of their therapeutic indication to include the heart failure. Despite their clinical benefits, warnings about adverse events have been implemented by Regulatory Agencies in the product's information since their introduction to the market. In particular, SGLT2 inhibitors have shown a strong impact on a high number of risk factors. They can cause hypoglycaemia, hypotension, lower limb amputation, fractures, genito-urinary infections, and diabetic ketoacidosis with different frequencies of onset. Despite some of these events are rare, they can lead to serious and dangerous complications, highlighting the importance of a strict monitoring of patients. Overall, SLGT-2 inhibitors are effective antidiabetic drugs with favorable advantages in renal and cardiovascular protection, and with a generally well-tolerated safety profile. This review aims to summarize the safety profile of SGLT2 inhibitors available in the market.
PubMed: 36211584
DOI: 10.3389/fcvm.2022.1010693 -
Pediatric Nephrology (Berlin, Germany) Apr 2019Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na-dependent phosphate... (Review)
Review
Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH) vitamin D as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date.
Topics: Animals; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Genetic Predisposition to Disease; Heredity; Humans; Kidney Tubules, Proximal; Mutation; Pedigree; Phenotype; Phosphates; Prognosis; Renal Reabsorption; Renal Tubular Transport, Inborn Errors; Risk Assessment; Risk Factors; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type III; Sodium-Phosphate Cotransporter Proteins, Type IIa; Sodium-Phosphate Cotransporter Proteins, Type IIc
PubMed: 29275531
DOI: 10.1007/s00467-017-3873-3 -
American Journal of Physiology. Renal... Jan 2021Sexual dimorphic variations are present in many aspects of biology and involve the structure and/or function of nearly every organ system. Acid-base homeostasis is...
Sexual dimorphic variations are present in many aspects of biology and involve the structure and/or function of nearly every organ system. Acid-base homeostasis is critical for optimal health, and renal ammonia metabolism has a major role in the maintenance of acid-base homeostasis. Recent studies have shown sex-dependent differences in renal ammonia metabolism with regard to both basal ammonia excretion and the response to an exogenous acid load. These sexual dimorphisms are associated with structural changes in the proximal tubule and the collecting duct and variations in the expression of multiple proteins involved in ammonia metabolism and transport. Studies using orchiectomy-induced testosterone deficiency and physiological testosterone replacement have shown that testosterone underlies much of the sex-dependent differences in the proximal tubule. This parallels the finding that the canonical testosterone target receptor, androgen receptor (AR), is present exclusively in the proximal tubule. Thus testosterone, possibly acting through AR activation, regulates multiple components of renal structure and ammonia metabolism. The lack of detectable AR in the remainder of the nephron and collecting duct suggests that some dimorphisms in renal structure and ammonia transporter expression are mediated through mechanisms other than direct testosterone-dependent AR activation. A better understanding of the mechanism and biological implications of sex's effect on renal structure and ammonia metabolism is critical for optimizing our ability to care for both men and women with acid-base disturbances.
Topics: Acid-Base Equilibrium; Ammonia; Animals; Female; Humans; Hydrogen-Ion Concentration; Kidney Tubules, Proximal; Male; Membrane Transport Proteins; Receptors, Androgen; Renal Elimination; Renal Reabsorption; Sex Characteristics; Sex Factors; Testosterone
PubMed: 33308019
DOI: 10.1152/ajprenal.00531.2020