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Frontiers in Physiology 2023The kidney is the key organ responsible for maintaining the body's water and electrolyte homeostasis. About 99% of the primary urine filtered from the Bowman's capsule... (Review)
Review
The kidney is the key organ responsible for maintaining the body's water and electrolyte homeostasis. About 99% of the primary urine filtered from the Bowman's capsule is reabsorbed along various renal tubules every day, with only 1-2 L of urine excreted. Aquaporins (AQPs) play a vital role in water reabsorption in the kidney. Currently, a variety of molecules are found to be involved in the process of urine concentration by regulating the expression or activity of AQPs, such as antidiuretic hormone, renin-angiotensin-aldosterone system (RAAS), prostaglandin, and several nuclear receptors. As the main bile acid receptors, farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor 1 (TGR5) play important roles in bile acid, glucose, lipid, and energy metabolism. In the kidney, FXR and TGR5 exhibit broad expression across all segments of renal tubules, and their activation holds significant therapeutic potential for numerous acute and chronic kidney diseases through alleviating renal lipid accumulation, inflammation, oxidative stress, and fibrosis. Emerging evidence has demonstrated that the genetic deletion of FXR or TGR5 exhibits increased basal urine output, suggesting that bile acid receptors play a critical role in urine concentration. Here, we briefly summarize the function of bile acid receptors in renal water reabsorption and urine concentration.
PubMed: 38033333
DOI: 10.3389/fphys.2023.1322288 -
Frontiers in Medicine 2021Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in... (Review)
Review
Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.
PubMed: 34988095
DOI: 10.3389/fmed.2021.777861 -
International Journal of Molecular... Sep 2022This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium-glucose co-transporter 2 (SGLT2) inhibitors,... (Review)
Review
This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium-glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium-hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.
Topics: Acetazolamide; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Furosemide; Glomerular Filtration Rate; Glucose; Humans; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchanger 3
PubMed: 36232506
DOI: 10.3390/ijms231911203 -
Biomedicine & Pharmacotherapy =... Sep 2023Diabetic kidney disease (DKD) is a prevalent complication of diabetes and a major secondary factor leading to end-stage renal disease. The kidney, a vital organ, is... (Review)
Review
Diabetic kidney disease (DKD) is a prevalent complication of diabetes and a major secondary factor leading to end-stage renal disease. The kidney, a vital organ, is composed of a heterogeneous group of intrinsic cells, including glomerular endothelial cells, podocytes, mesangial cells, tubular epithelial cells, and interstitial fibroblasts. In the context of DKD, hyperglycemia elicits direct or indirect injury to these intrinsic cells, leading to their structural and functional changes, such as cell proliferation, apoptosis, and transdifferentiation. The dynamic remodeling of intrinsic cells represents an adaptive response to stimulus during the pathogenesis of diabetic kidney disease. However, the persistent stimulus may trigger an irreversible remodeling, leading to fibrosis and functional deterioration of the kidney. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of hypoglycemic drugs, exhibit efficacy in reducing blood glucose levels by curtailing renal tubular glucose reabsorption. Furthermore, SGLT2 inhibitors have been shown to modulate intrinsic cell remodeling in the kidney, ameliorate kidney structure and function, and decelerate DKD progression. This review will elaborate on the intrinsic cell remodeling in DKD and the underlying mechanism of SGLT2 inhibitors in modulating it from the perspective of the renal intrinsic cell, providing insights into the pathogenesis of DKD and the renal protective action of SGLT2 inhibitors.
Topics: Humans; Diabetic Nephropathies; Sodium-Glucose Transporter 2 Inhibitors; Endothelial Cells; Kidney; Hypoglycemic Agents; Glucose; Diabetes Mellitus, Type 2
PubMed: 37385209
DOI: 10.1016/j.biopha.2023.115025 -
American Journal of Hypertension Aug 2020Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure,... (Review)
Review
Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure, renal disease, stroke, and cancer. Therefore, considerable research has been expended on the mechanism of sodium handling based on the current concepts of sodium balance. The studies have necessarily relied on relatively short-term experiments and focused on extremes of salt intake in humans. Ultra-long-term salt balance has received far less attention. We performed long-term salt balance studies at intakes of 6, 9, and 12 g/day and found that although the kidney remains the long-term excretory gate, tissue and plasma sodium concentrations are not necessarily the same and that urinary salt excretion does not necessarily reflect total-body salt content. We found that to excrete salt, the body makes a great effort to conserve water, resulting in a natriuretic-ureotelic principle of salt excretion. Of note, renal sodium handling is characterized by osmolyte excretion with anti-parallel water reabsorption, a state-of-affairs that is achieved through the interaction of multiple organs. In this review, we discuss novel sodium and water balance concepts in reference to our ultra-long-term study. An important key to understanding body sodium metabolism is to focus on water conservation, a biological principle to protect from dehydration, since excess dietary salt excretion into the urine predisposes to renal water loss because of natriuresis. We believe that our research direction is relevant not only to salt balance but also to cardiovascular regulatory mechanisms.
Topics: Animals; Appetite; Body Water; Cardiovascular System; Drinking; Energy Metabolism; Humans; Infradian Rhythm; Kidney; Kidney Concentrating Ability; Liver; Muscle, Skeletal; Natriuresis; Renal Elimination; Sodium; Sodium Chloride, Dietary; Thirst; Water-Electrolyte Balance
PubMed: 32198504
DOI: 10.1093/ajh/hpaa049 -
FASEB Journal : Official Publication of... Apr 2023Through its classic ATP-dependent ion-pumping function, basolateral Na/K-ATPase (NKA) generates the Na gradient that drives apical Na reabsorption in the renal proximal...
Through its classic ATP-dependent ion-pumping function, basolateral Na/K-ATPase (NKA) generates the Na gradient that drives apical Na reabsorption in the renal proximal tubule (RPT), primarily through the Na /H exchanger (NHE3). Accordingly, activation of NKA-mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na /HCO cotransporter (NBCe1A). Urine output and absolute Na excretion decreased by 65%, driven by increased RPT Na reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3 mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na reabsorption by regulating key apical and basolateral Na transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP-driven function of basolateral Na reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption.
Topics: Animals; Mice; Sodium; Sodium-Hydrogen Exchanger 3; Kidney Tubules; Sodium-Potassium-Exchanging ATPase; Adenosine Triphosphate
PubMed: 36856735
DOI: 10.1096/fj.202200785RR -
Channels (Austin, Tex.) Dec 2020TRPC3 is a Ca-permeable cation channel commonly activated by the G-protein coupled receptors (GPCR) and mechanical distortion of the plasma membrane. TRPC3-mediated Ca... (Review)
Review
TRPC3 is a Ca-permeable cation channel commonly activated by the G-protein coupled receptors (GPCR) and mechanical distortion of the plasma membrane. TRPC3-mediated Ca influx has been implicated in a variety of signaling processes in both excitable and non-excitable cells. Kidneys play a commanding role in maintaining whole-body homeostasis and setting blood pressure. TRPC3 is expressed abundantly in the renal vasculature and in epithelial cells, where it is well positioned to mediate signaling and transport functions in response to GPCR-dependent endocrine stimuli. In addition, TRPC3 could be activated by mechanical forces resulting from dynamic changes in the renal tubule fluid flow and osmolarity. This review critically analyzes the available published evidence of the physiological roles of TRPC3 in different parts of the kidney and describes the pathophysiological ramifications of TRPC3 ablation. We also speculate how this evidence could be further translated into the clinic.
Topics: Animals; Calcium; Humans; Kidney; Osmolar Concentration; Signal Transduction; TRPC Cation Channels
PubMed: 32787494
DOI: 10.1080/19336950.2020.1804153 -
Frontiers in Pharmacology 2022Hyperuricemia is the result of increased production and/or underexcretion of uric acid. Hyperuricemia has been epidemiologically associated with multiple comorbidities,... (Review)
Review
Hyperuricemia is the result of increased production and/or underexcretion of uric acid. Hyperuricemia has been epidemiologically associated with multiple comorbidities, including metabolic syndrome, gout with long-term systemic inflammation, chronic kidney disease, urolithiasis, cardiovascular disease, hypertension, rheumatoid arthritis, dyslipidemia, diabetes/insulin resistance and increased oxidative stress. Dysregulation of xanthine oxidoreductase (XOD), the enzyme that catalyzes uric acid biosynthesis primarily in the liver, and urate transporters that reabsorb urate in the renal proximal tubules (URAT1, GLUT9, OAT4 and OAT10) and secrete urate (ABCG2, OAT1, OAT3, NPT1, and NPT4) in the renal tubules and intestine, is a major cause of hyperuricemia, along with variations in the genes encoding these proteins. The first-line therapeutic drugs used to lower serum uric acid levels include XOD inhibitors that limit uric acid biosynthesis and uricosurics that decrease urate reabsorption in the renal proximal tubules and increase urate excretion into the urine and intestine urate transporters. However, long-term use of high doses of these drugs induces acute kidney disease, chronic kidney disease and liver toxicity. Therefore, there is an urgent need for new nephroprotective drugs with improved safety profiles and tolerance. The current systematic review summarizes the characteristics of major urate transporters, the mechanisms underlying the pathogenesis of hyperuricemia, and the regulation of uric acid biosynthesis and transport. Most importantly, this review highlights the potential mechanisms of action of some naturally occurring bioactive compounds with antihyperuricemic and nephroprotective potential isolated from various medicinal plants.
PubMed: 36483739
DOI: 10.3389/fphar.2022.1026246 -
Frontiers in Endocrinology 2023Visceral adipose tissue plays a central role in obesity and metabolic syndrome and is an independent risk factor for both cardiovascular and metabolic disorders.... (Review)
Review
Visceral adipose tissue plays a central role in obesity and metabolic syndrome and is an independent risk factor for both cardiovascular and metabolic disorders. Increased visceral adipose tissue promotes adipokine dysregulation and insulin resistance, leading to several health issues, including systemic inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system. Moreover, an increase in adipose tissue directly and indirectly affects the kidneys by increasing renal sodium reabsorption, causing glomerular hyperfiltration and hypertrophy, which leads to increased proteinuria and kidney fibrosis/dysfunction. Although the interest in the adverse effects of obesity on renal diseases has grown exponentially in recent years, the relationship between obesity and renal prognosis remains controversial. This may be attributed to the long clinical course of obesity, numerous obesity-related metabolic complications, and patients' attributes. Multiple individual attributes influencing the pathophysiology of fat accumulation make it difficult to understand obesity. In such cases, it may be effective to elucidate the pathophysiology by conducting research tailored to individual attributes from the perspective of attribute-based medicine/personalized medicine. We consider the appropriate use of clinical indicators necessary, according to attributes such as chronic kidney disease stage, level of visceral adipose tissue accumulation, age, and sex. Selecting treatments and clinical indicators based on individual attributes will allow for advancements in the clinical management of patients with obesity and chronic kidney disease. In the clinical setting of obesity-related nephropathy, it is first necessary to accumulate attribute-based studies resulting from the accurate evaluation of visceral fat accumulation to establish evidence for promoting personalized medicine.
Topics: Humans; Intra-Abdominal Fat; Obesity; Metabolic Syndrome; Kidney; Renal Insufficiency, Chronic
PubMed: 36843595
DOI: 10.3389/fendo.2023.1097596 -
Frontiers in Endocrinology 2022In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an... (Review)
Review
In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium-glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin-angiotensin-aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Glomerular Filtration Rate; Glucose; Humans; Kidney Glomerulus; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 35663316
DOI: 10.3389/fendo.2022.872918