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Nutrients Feb 2024Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular... (Review)
Review
Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, which are instrumental in assessing bone remodeling. This comprehensive evaluation aids in detecting disorders arising from imbalances between bone formation and reabsorption. Osteoporosis, characterized by a reduction in bone mass and strength leading to heightened bone fragility and susceptibility to fractures, is one of the more prevalent chronic diseases. Some epidemiological studies, especially in patients with chronic kidney disease (CKD), have identified an association between osteoporosis and vascular calcification. Notably, low bone mineral density has been linked to an increased incidence of aortic calcification, with shared molecules, mechanisms, and pathways between the two processes. Certain molecules emerging from these shared pathways can serve as biomarkers for bone and mineral metabolism. Detecting and evaluating these alterations early is crucial, requiring the identification of biomarkers that are reliable for early intervention. While traditional biomarkers for bone remodeling and vascular calcification exist, they suffer from limitations such as low specificity, low sensitivity, and conflicting results across studies. In response, efforts are underway to explore new, more specific biomarkers that can detect alterations at earlier stages. The aim of this review is to comprehensively examine some of the emerging biomarkers in mineral metabolism and their correlation with bone mineral density, fracture risk, and vascular calcification as well as their potential use in clinical practice.
Topics: Humans; Chronic Kidney Disease-Mineral and Bone Disorder; Osteoporosis; Bone Density; Renal Insufficiency, Chronic; Fractures, Bone; Vascular Calcification; Biomarkers; Minerals
PubMed: 38474734
DOI: 10.3390/nu16050605 -
Cells Mar 2024The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does... (Review)
Review
A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.
The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.
Topics: Humans; Rats; Animals; Cardiovascular Diseases; Metabolic Syndrome; Uricosuric Agents; Uric Acid; Renal Insufficiency, Chronic; Glucose; Organic Anion Transporters; Benzothiazoles
PubMed: 38474414
DOI: 10.3390/cells13050450 -
International Journal of Molecular... Mar 2024The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the... (Review)
Review
The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the reabsorption of proteins, electrolytes, cytokines, growth factors, and immune cells. Pathological conditions, including tissue damage, excessive interstitial fluid, high blood glucose levels, and inflammation, can initiate lymphangiogenesis-the formation of new lymphatic vessels. This process is associated with various kidney diseases, including polycystic kidney disease, hypertension, ultrafiltration challenges, and complications post-organ transplantation. Although lymphangiogenesis has beneficial effects in removing excess fluid and immune cells, it may also contribute to inflammation and fibrosis within the kidneys. In this review, we aim to discuss the biology of the lymphatic system, from its development and function to its response to disease stimuli, with an emphasis on renal pathophysiology. Furthermore, we explore how innovative treatments targeting the lymphatic system could potentially enhance the management of kidney diseases.
Topics: Humans; Lymphangiogenesis; Kidney; Nephritis; Lymphatic System; Inflammation; Kidney Diseases; Fibrosis
PubMed: 38474100
DOI: 10.3390/ijms25052853 -
The Journal of Pharmacology and... Mar 2024A problem for patients with diabetes is the rise of complications, such as peripheral neuropathy, nephropathy and retinopathy. Among them, peripheral neuropathy,...
A problem for patients with diabetes is the rise of complications, such as peripheral neuropathy, nephropathy and retinopathy. Among them, peripheral neuropathy, characterized by numbness and/or hypersensitivity to pain in the extremities, is likely to develop in the early stages of diabetes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor, exerts hypoglycemic effects by preventing glucose reabsorption in proximal tubular cells. EMPA can improve cardiovascular and renal outcomes in diabetic patients, but its suppressive effect on the development of diabetic neuropathy remains unclear. In this study, we demonstrated that optimizing the dosing schedule of EMPA suppressed the development of pain hypersensitivity in streptozotocin (STZ)-induced diabetic model mice maintained under standardized light/dark cycle conditions. A single intraperitoneal administration of STZ to mice induced hyperglycemia accompanied by pain hypersensitivity. Although EMPA did not exert anti-hypersensitivity effect on STZ-induced diabetic mice after the establishment of neuropathic pain, the development of pain hypersensitivity in the diabetic mice was significantly suppressed by daily oral administration of EMPA at the beginning of the dark phase. On the other hand, the suppressive effect was not observed when EMPA was administered at the beginning of the light phase. The hypoglycemic effect of EMPA and its stimulatory effect on urinary glucose excretion were also enhanced by the administration of the drug at the beginning of the dark phase. Nocturnal mice consumed their food mainly during the dark phase. Our results support the notion that morning administration of EMPA may be effective in suppressing the development of peripheral neuropathy in diabetic patients. Empagliflozin, a sodium-glucose cotransporter-2 inhibitor suppressed the development of neuropathic pain hypersensitivity in streptozotocin-induced diabetic model mice in a dosing time-dependent manner.
PubMed: 38458768
DOI: 10.1124/jpet.123.001856 -
Comparative Biochemistry and... Jun 2024Insect Malpighian tubules contribute to Ca homeostasis via Ca storage in intracellular compartments, Ca secretion into the tubule lumen, and Ca reabsorption into the...
Effects of dietary calcium (Ca) and blood feeding on the immunochemical expression of the plasma membrane Ca-ATPase (PMCA) in Malpighian tubules of adult female mosquitoes (Aedes aegypti).
Insect Malpighian tubules contribute to Ca homeostasis via Ca storage in intracellular compartments, Ca secretion into the tubule lumen, and Ca reabsorption into the hemolymph. A plasma membrane Ca-ATPase (PMCA) is hypothesized to be a Ca-transporter involved in renal Ca transport of insects, however few studies have investigated its immunochemical expression in Malpighian tubules. Here we characterized the abundance and localization of PMCA-like immunoreactivity in Malpighian tubules of adult female mosquitoes Aedes aegypti using an antibody against Drosophila melanogaster PMCA. Western blotting revealed expression of a relatively abundant 109 kDa isoform and a relatively sparse 115 kDa isoform. Feeding mosquitoes 10% sucrose with 50 mM CaCl for 7 days did not affect PMCA immunoreactivity. However, at 24, 48, and 96 h post-blood feeding (PBF), the relative abundance of the 109 kDa isoform decreased while that of the 115 kDa isoform increased. Immunolabeling of Malpighian tubules revealed PMCA-like immunoreactivity in both principal and stellate cells; principal cell labeling was intracellular, whereas stellate cell labeling was along the basal membrane. Blood feeding enhanced immunolabeling of PMCA in stellate cells but weakened that in principal cells. Moreover, a unique apicolateral pattern of PMCA-like immunolabeling occurred in principal cells of the proximal segment at 24 h PBF, suggesting potential trafficking to septate junctions. Our results suggest PMCA isoforms are differentially expressed and localized in mosquito Malpighian tubules where they contribute to redistributing tubule Ca during blood meal processing.
Topics: Female; Animals; Aedes; Adenosine Triphosphatases; Malpighian Tubules; Calcium, Dietary; Drosophila melanogaster; Cell Membrane; Protein Isoforms
PubMed: 38458419
DOI: 10.1016/j.cbpa.2024.111623 -
Frontiers in Physiology 2024Efferent sympathetic nerve fibers regulate several renal functions activating norepinephrine receptors on tubular epithelial cells. Of the beta-adrenoceptors (β-ARs),...
Efferent sympathetic nerve fibers regulate several renal functions activating norepinephrine receptors on tubular epithelial cells. Of the beta-adrenoceptors (β-ARs), we previously demonstrated the renal expression of β3-AR in the thick ascending limb (TAL), the distal convoluted tubule (DCT), and the collecting duct (CD), where it participates in salt and water reabsorption. Here, for the first time, we reported β3-AR expression in the CD intercalated cells (ICCs), where it regulates acid-base homeostasis. Co-localization of β3-AR with either proton pump H-ATPase or Cl/HCO exchanger pendrin revealed β3-AR expression in type A, type B, non-A, and non-B ICCs in the mouse kidney. We aimed to unveil the possible regulatory role of β3-AR in renal acid-base homeostasis, in particular in modulating the expression, subcellular localization, and activity of the renal H-ATPase, a key player in this process. The abundance of H-ATPase was significantly decreased in the kidneys of β3-AR compared with those of β3-AR mice. In particular, H-ATPase reduction was observed not only in the CD but also in the TAL and DCT, which contribute to acid-base transport in the kidney. Interestingly, we found that in , the absence of β3-AR reduced the kidneys' ability to excrete excess proton in the urine during an acid challenge. Using stimulation of mouse kidney slices, we proved that the β3-AR activation promoted H-ATPase apical expression in the epithelial cells of β3-AR-expressing nephron segments, and this was prevented by β3-AR antagonism or PKA inhibition. Moreover, we assessed the effect of β3-AR stimulation on H-ATPase activity by measuring the intracellular pH recovery after an acid load in β3-AR-expressing mouse renal cells. Importantly, β3-AR agonism induced a 2.5-fold increase in H-ATPase activity, and this effect was effectively prevented by β3-AR antagonism or by inhibiting either H-ATPase or PKA. Of note, in urine samples from patients treated with a β3-AR agonist, we found that β3-AR stimulation increased the urinary excretion of H-ATPase, likely indicating its apical accumulation in tubular cells. These findings demonstrate that β3-AR activity positively regulates the expression, plasma membrane localization, and activity of H-ATPase, elucidating a novel physiological role of β3-AR in the sympathetic control of renal acid-base homeostasis.
PubMed: 38455846
DOI: 10.3389/fphys.2024.1304375 -
Scientific Reports Mar 2024Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid...
Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15-60 mL/min/1.73 m. The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13-2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney.
Topics: Humans; Uric Acid; Retrospective Studies; Kidney; Glomerular Filtration Rate; Renal Insufficiency, Chronic
PubMed: 38429496
DOI: 10.1038/s41598-024-55809-9 -
Pharmaceuticals (Basel, Switzerland) Feb 2024Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are... (Review)
Review
Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake. High renal accumulation of radioactive compounds may lead to nephrotoxicity, and therefore, the kidneys are often the dose-limiting organs in TRT with these radioligands. Over the years, different strategies have been developed aiming for reduced kidney retention and enhanced therapeutic efficacy of radioligands. In this review, we will give an overview of the efforts and achievements of the used strategies, with focus on the therapeutic potential of low-to-moderate-molecular-weight molecules. Among the strategies discussed here is coadministration of compounds that compete for binding to the endocytic receptors in the proximal tubuli. In addition, the influence of altering the molecular design of radiolabeled ligands on pharmacokinetics is discussed, which includes changes in their physicochemical properties and implementation of cleavable linkers or albumin-binding moieties. Furthermore, we discuss the influence of chelator and radionuclide choice on reabsorption of radioligands by the kidneys.
PubMed: 38399470
DOI: 10.3390/ph17020256 -
Journal of Clinical Medicine Feb 2024Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women impacting their reproductive, mental, and metabolic health. Insulin... (Review)
Review
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women impacting their reproductive, mental, and metabolic health. Insulin resistance is a major driver of the pathophysiology of PCOS. There are several challenges with the management of this complex disorder including insufficient treatment options. Over the past 88 years, multiple hormonal and non-hormonal medications have been tried to treat the various components of this syndrome and there is no FDA (Food and Drug Administration)-approved medication specifically for PCOS yet. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have a unique mechanism of inhibiting the coupled reabsorption of sodium and glucose in renal proximal convoluted tubules. This review aims to examine the efficacy and side-effect profile of SGLT-2 inhibitors in patients with PCOS. In a limited number of studies, SGLT-2 inhibitors appear to be effective in improving menstrual frequency, reducing body weight and total fat mass, lowering total testosterone and DHEAS levels, and improving some glycemic indices in women with PCOS. SGLT2 inhibitors are generally well tolerated. With future research, it is possible that SGLT-2 inhibitors could become a key therapeutic option for PCOS.
PubMed: 38398368
DOI: 10.3390/jcm13041056 -
Cell & Bioscience Feb 2024Sodium-Glucose cotransporter 1 and 2 (SGLT1/2) belong to the family of glucose transporters, encoded by SLC5A1 and SLC5A2, respectively. SGLT2 is almost exclusively...
BACKGROUND
Sodium-Glucose cotransporter 1 and 2 (SGLT1/2) belong to the family of glucose transporters, encoded by SLC5A1 and SLC5A2, respectively. SGLT2 is almost exclusively expressed in the renal proximal convoluted tubule cells. SGLT1 is expressed in the kidneys but also in other organs throughout the body. Many SGLT inhibitor drugs have been developed based on the mechanism of blocking glucose (re)absorption mediated by SGLT1/2, and several have gained major regulatory agencies' approval for treating diabetes. Intriguingly these drugs are also effective in treating diseases beyond diabetes, for example heart failure and chronic kidney disease. We recently discovered that SGLT1 is upregulated in the airway epithelial cells derived from patients of cystic fibrosis (CF), a devastating genetic disease affecting greater than 70,000 worldwide.
RESULTS
In the present work, we show that the SGLT1 upregulation is coupled with elevated endoplasmic reticulum (ER) stress response, indicated by activation of the primary ER stress senor inositol-requiring protein 1α (IRE1α) and the ER stress-induced transcription factor X-box binding protein 1 (XBP1), in CF epithelial cells, and in epithelial cells of other stress conditions. Through biochemistry experiments, we demonstrated that the spliced form of XBP1 (XBP1s) acts as a transcription factor for SLC5A1 by directly binding to its promoter region. Targeting this ER stress → SLC5A1 axis by either the ER stress inhibitor Rapamycin or the SGLT1 inhibitor Sotagliflozin was effective in attenuating the ER stress response and reducing the SGLT1 level in these cellular model systems.
CONCLUSIONS
The present work establishes a causal relationship between ER stress and SGLT1 upregulation and provides a mechanistic explanation why SGLT inhibitor drugs benefit diseases beyond diabetes.
PubMed: 38388523
DOI: 10.1186/s13578-024-01203-x