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Current Opinion in Nephrology and... Sep 2016The paracellular pathway through the tight junction provides an important route for chloride reabsorption in the collecting duct of the kidney. This review describes... (Review)
Review
PURPOSE OF REVIEW
The paracellular pathway through the tight junction provides an important route for chloride reabsorption in the collecting duct of the kidney. This review describes recent findings of how defects in paracellular chloride permeation pathway may cause kidney diseases and how such a pathway may be regulated to maintain normal chloride homeostasis.
RECENT FINDINGS
The tight junction in the collecting duct expresses two important claudin genes - claudin-4 and claudin-8. Transgenic knockout of either claudin gene causes hypotension, hypochloremia, and metabolic alkalosis in experimental animals. The claudin-4 mediated chloride permeability can be regulated by a protease endogenously expressed by the collecting duct cell - channel-activating protease 1. Channel-activating protease 1 regulates the intercellular interaction of claudin-4 and its membrane stability. Kelch-like 3, previously identified as a causal gene for Gordon's syndrome, also known as pseudohypoaldosteronism II, directly interacts with claudin-8 and regulates its ubiquitination and degradation. The dominant pseudohypoaldosteronism-II mutation (R528H) in Kelch-like 3 abolishes claudin-8 binding, ubiquitination, and degradation.
SUMMARY
The paracellular chloride permeation pathway in the kidney is an important but understudied area in nephrology. It plays vital roles in renal salt handling and regulation of extracellular fluid volume and blood pressure. Two claudin proteins, claudin-4 and claudin-8, contribute to the function of this paracellular pathway. Deletion of either claudin protein from the collecting duct causes renal chloride reabsorption defects and low blood pressure. Claudins can be regulated on posttranslational levels by several mechanisms involving protease and ubiquitin ligase. Deregulation of claudins may cause human hypertension as exemplified in the Gordon's syndrome.
Topics: Adaptor Proteins, Signal Transducing; Animals; Blood Pressure; Carrier Proteins; Chlorides; Claudin-4; Claudins; Humans; Kidney Diseases; Kidney Tubules, Collecting; Microfilament Proteins; Permeability; Pseudohypoaldosteronism; Renal Reabsorption; Serine Endopeptidases; Tight Junctions
PubMed: 27490784
DOI: 10.1097/MNH.0000000000000253 -
Vitamins and Hormones 2016A history of vitamin D has been provided, dating from the earliest description of rickets, the disease resulting from vitamin D deficiency, to a current understanding of... (Review)
Review
A history of vitamin D has been provided, dating from the earliest description of rickets, the disease resulting from vitamin D deficiency, to a current understanding of vitamin D metabolism and the mechanism of action of its hormonal form in regulating gene expression in target organs. Vitamin D is produced in skin by impact of 280-310 nm light on 7-dehydrocholesterol. The vitamin D is then converted in the liver to a circulating form, 25-hydroxyvitamin D that is converted largely, if not exclusively, in the kidney to the final hormone, 1α,25-dihydroxyvitamin D. This hormone functions through a nuclear receptor that regulates expression of key genes in target organs. Among its many resulting functions are increased intestinal calcium and phosphate absorption, bone calcium mobilization, and renal reabsorption of calcium. The resultant increase in serum calcium and phosphate supports bone mineralization, curing rickets, and osteomalacia. There are many other functions of vitamin D that remain to be described that contribute to its health supporting role.
Topics: Animals; Calcium; Humans; Vitamin D; Vitamin D Deficiency
PubMed: 26827946
DOI: 10.1016/bs.vh.2015.11.001 -
American Journal of Physiology. Renal... Jul 2017Glucose homeostasis is highly controlled, and the function of the kidney plays an integral role in this process. The exquisite control of blood glucose relies, in part,... (Review)
Review
Glucose homeostasis is highly controlled, and the function of the kidney plays an integral role in this process. The exquisite control of blood glucose relies, in part, on renal glucose filtration, renal glucose reabsorption, and renal gluconeogenesis. Particularly critical to maintaining glucose homeostasis is the renal reabsorption of glucose; with ~162 g of glucose filtered by the kidney per day, it is imperative that the kidney have the ability to efficiently reabsorb nearly 100% of this glucose back in the bloodstream. In this review, we focus on this central process, highlighting the renal transporters and regulators involved in both the physiology and pathophysiology of glucose reabsorption.
Topics: Animals; Biomarkers; Blood Glucose; Gluconeogenesis; Glucose Transport Proteins, Facilitative; Homeostasis; Humans; Kidney; Kidney Diseases; Renal Reabsorption; Sodium-Glucose Transport Proteins
PubMed: 28356283
DOI: 10.1152/ajprenal.00046.2017 -
International Journal of Molecular... Apr 2024This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and... (Review)
Review
This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.
Topics: Humans; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Animals; Phosphates; Parathyroid Hormone; Antibodies, Monoclonal, Humanized; Vitamin D; Bone and Bones; Klotho Proteins
PubMed: 38732094
DOI: 10.3390/ijms25094875 -
Biochemical Pharmacology Feb 2016Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment...
Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM.
Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Membrane Transport Modulators; Models, Biological; Nephrons; Renal Reabsorption; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 26362302
DOI: 10.1016/j.bcp.2015.09.005 -
Advances in Therapy May 2020Hypophosphataemic rickets is a heterogeneous group of entities characterized by rickets or osteomalacia due to a phosphate deficit caused mainly by decreased renal... (Review)
Review
Hypophosphataemic rickets is a heterogeneous group of entities characterized by rickets or osteomalacia due to a phosphate deficit caused mainly by decreased renal reabsorption. They are also characterized by defective intestinal absorption of calcium and rickets or osteomalacia unresponsive to cholecalciferol. These metabolic alterations lead to growth retardation, bone pain and deformities, and short stature. For a correct diagnosis and treatment of all forms of rickets, the basic aspects of pathophysiology of the calcium-phosphorus metabolism and the relevance of the bone-kidney axis modulated by the presence of phosphaturic agents need to be known. Diagnosis of these diseases includes clinical assessment, blood and urine analytical tests, and bone x-ray. The aim of this article is to briefly describe the pathophysiology, signs, symptoms, and clinical forms of hypophosphataemic rickets, proposing a diagnosis algorithm that can help in the clinical practice.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Calcium; Child; Child, Preschool; Diagnosis, Differential; Female; Fibroblast Growth Factor-23; Humans; Infant; Infant, Newborn; Male; Middle Aged; Phosphates; Rickets, Hypophosphatemic; Symptom Assessment
PubMed: 32236869
DOI: 10.1007/s12325-019-01184-1 -
Molecular Genetics and Metabolism Nov 2015Carnitine is a hydrophilic quaternary amine that plays a number of essential roles in metabolism with the main function being the transport of long-chain fatty acids... (Review)
Review
Carnitine is a hydrophilic quaternary amine that plays a number of essential roles in metabolism with the main function being the transport of long-chain fatty acids from the cytosol to the mitochondrial matrix for β-oxidation. Carnitine can be endogenously synthesized. However, only a small fraction of carnitine is obtained endogenously while the majority is obtained from diet, mainly animal products. Carnitine is not metabolized and is excreted in urine. Carnitine homeostasis is regulated by efficient renal reabsorption that maintains carnitine levels within the normal range despite variabilities in dietary intake. Diseases occurring due to primary defects in carnitine metabolism and homeostasis are comprised in two groups: disorders of carnitine biosynthesis and carnitine transport defect. While the hallmark of carnitine transport defect is profound carnitine depletion, disorders of carnitine biosynthesis do not cause carnitine deficiency due to the fact that both carnitine obtained from diet and efficient renal carnitine reabsorption can maintain normal carnitine levels with the absence of endogenously synthesized carnitine. Carnitine transport defect phenotype encompasses a broad clinical spectrum including metabolic decompensation in infancy, cardiomyopathy in childhood, fatigability in adulthood, or absence of symptoms. The phenotypes associated with the carnitine transport defect result from the unavailability of enough carnitine to perform its functions particularly in fatty acid β-oxidation. Carnitine biosynthetic defects have been recently described and the phenotypic consequences of these defects are still emerging. Although these defects do not result in carnitine deficiency, they still could be associated with pathological phenotypes due to excess or deficiency of intermediate metabolites in the carnitine biosynthetic pathway and potential carnitine deficiency in early stages of life when brain and other organs develop. In addition to these two groups of primary carnitine defects, several metabolic diseases and medical conditions can result in excessive carnitine loss leading to a secondary carnitine deficiency.
Topics: Animals; Autism Spectrum Disorder; Biological Transport; Cardiomyopathies; Carnitine; Fatty Acids; Humans; Hyperammonemia; Metabolic Diseases; Mitochondria; Muscular Diseases
PubMed: 26385306
DOI: 10.1016/j.ymgme.2015.09.004 -
Scientific Reports Jan 2018Caveolin-1 (Cav1) is essential for the formation of caveolae. Little is known about their functional role in the kidney. We tested the hypothesis that caveolae modulate...
Caveolin-1 (Cav1) is essential for the formation of caveolae. Little is known about their functional role in the kidney. We tested the hypothesis that caveolae modulate renal salt and water reabsorption. Wild-type (WT) and Cav1-deficient (Cav1-/-) mice were studied. Cav1 expression and caveolae formation were present in vascular cells, late distal convoluted tubule and principal connecting tubule and collecting duct cells of WT but not Cav1-/- kidneys. Urinary sodium excretion was increased by 94% and urine flow by 126% in Cav1-/- mice (p < 0.05). A decrease in activating phosphorylation of the Na-Cl cotransporter (NCC) of the distal convoluted tubule was recorded in Cav1-/- compared to WT kidneys (-40%; p < 0.05). Isolated intrarenal arteries from Cav1-/- mice revealed a fourfold reduction in sensitivity to phenylephrine (p < 0.05). A significantly diminished maximal contractile response (-13%; p < 0.05) was suggestive of enhanced nitric oxide (NO) availability. In line with this, the abundance of endothelial NO synthase (eNOS) was increased in Cav1-/- kidneys +213%; p < 0.05) and cultured caveolae-deprived cells showed intracellular accumulation of eNOS, compared to caveolae-intact controls. Our results suggest that renal caveolae help to conserve water and electrolytes via modulation of NCC function and regulation of vascular eNOS.
Topics: Animals; Caveolin 1; Cells, Cultured; Endothelium, Vascular; Humans; Kidney; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Renal Artery; Renal Reabsorption; Sodium; Sodium-Calcium Exchanger
PubMed: 29323234
DOI: 10.1038/s41598-017-19071-6 -
Journal of Medicinal Chemistry Jun 2021Drug reabsorption following biliary excretion is well-known as enterohepatic recirculation (EHR). Renal tubular reabsorption (RTR) following renal excretion is also... (Review)
Review
Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs.
Drug reabsorption following biliary excretion is well-known as enterohepatic recirculation (EHR). Renal tubular reabsorption (RTR) following renal excretion is also common but not easily assessed. Intestinal excretion (IE) and enteroenteric recirculation (EER) have not been recognized as common disposition mechanisms for metabolically stable and permeable drugs. IE and intestinal reabsorption (IR:EHR/EER), as well as RTR, are governed by dug concentration gradients, passive diffusion, active transport, and metabolism, and together they markedly impact disposition and pharmacokinetics (PK) of small molecule drugs. Disruption of IE, IR, or RTR through applications of active charcoal (AC), transporter knockout (KO), and transporter inhibitors can lead to changes in PK parameters. The impacts of intestinal and renal reabsorption on PK are under-appreciated. Although IE and EER/RTR can be an intrinsic drug property, there is no apparent strategy to optimize compounds based on this property. This review seeks to improve understanding and applications of IE, IR, and RTR mechanisms.
Topics: Animals; Digoxin; Half-Life; Humans; Intestinal Mucosa; Kidney Tubules; Pyrazoles; Pyridines; Pyridones; Renal Reabsorption; Small Molecule Libraries; Triazoles
PubMed: 34010555
DOI: 10.1021/acs.jmedchem.0c01720 -
International Journal of Molecular... Apr 2024To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This... (Review)
Review
To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.
Topics: Humans; Phosphates; Animals; Renal Reabsorption; Kidney; Kidney Tubules, Proximal
PubMed: 38731904
DOI: 10.3390/ijms25094684