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Nutrients May 2024Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form... (Review)
Review
Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form calcifediol (25(OH)D) in the liver, then to 1,25(OH)D (calcitriol) in the kidney. Alongside the parathyroid hormone, calcitriol regulates neuro-musculoskeletal activities by tightly controlling blood-ionized calcium concentrations through intestinal calcium absorption, renal tubular reabsorption, and skeletal mineralization. Beyond its classical roles, evidence underscores the impact of vitamin D on the prevention and reduction of the severity of diverse conditions such as cardiovascular and metabolic diseases, autoimmune disorders, infection, and cancer. Peripheral target cells, like immune cells, obtain vitamin D and 25(OH)D through concentration-dependent diffusion from the circulation. Calcitriol is synthesized intracellularly in these cells from these precursors, which is crucial for their protective physiological actions. Its deficiency exacerbates inflammation, oxidative stress, and increased susceptibility to metabolic disorders and infections; deficiency also causes premature deaths. Thus, maintaining optimal serum levels above 40 ng/mL is vital for health and disease prevention. However, achieving it requires several times more than the government's recommended vitamin D doses. Despite extensive published research, recommended daily intake and therapeutic serum 25(OH)D concentrations have lagged and are outdated, preventing people from benefiting. Evidence suggests that maintaining the 25(OH)D concentrations above 40 ng/mL with a range of 40-80 ng/mL in the population is optimal for disease prevention and reducing morbidities and mortality without adverse effects. The recommendation for individuals is to maintain serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) for optimal clinical outcomes. Insights from metabolomics, transcriptomics, and epigenetics offer promise for better clinical outcomes from vitamin D sufficiency. Given its broader positive impact on human health with minimal cost and little adverse effects, proactively integrating vitamin D assessment and supplementation into clinical practice promises significant benefits, including reduced healthcare costs. This review synthesized recent novel findings related to the physiology of vitamin D that have significant implications for disease prevention.
Topics: Humans; Vitamin D; Vitamin D Deficiency; Dietary Supplements; Cardiovascular Diseases
PubMed: 38892599
DOI: 10.3390/nu16111666 -
Clinica Chimica Acta; International... Jun 2024GATM-related Fanconi renotubular syndrome 1 (FRTS1) is a form of renal Fanconi syndrome (RFS), which is a disorder of solute and water reabsorption caused by defects in...
GATM-related Fanconi renotubular syndrome 1 (FRTS1) is a form of renal Fanconi syndrome (RFS), which is a disorder of solute and water reabsorption caused by defects in the function of the entire proximal tubule. Recent findings reveal the molecular basis of FRTS1: Intramitochondrial fiber aggregation triggered by mutant GATM provides a starting point for proximal tubule damage and drives disease progression. As a rare and newly recognized inherited kidney disease, the complex manifestations of FRTS1 are easily underdiagnosed or misdiagnosed. We discuss the complex phenotype of a 26-year-old woman with onset in infancy and a long history of hypophosphatemic rickets. We also identified a novel heterozygous missense variant in the GATM gene in this patient. The novel variant and phenotype we report expand the disease spectrum of FRTS1. We recommend screening for GATM in children with RFS, especially in patients with resistant rickets who have previously had negative genetic testing. In addition, we found pathological deposition of mutant GATM proteins within mitochondria in the patient's urinary sediment cells by a combination of electron microscopy and immunofluorescence. This unique urine cytology experiment has the potential to be a valuable tool for identifying patients with RRTS1.
PubMed: 38876250
DOI: 10.1016/j.cca.2024.119812 -
Nephrology, Dialysis, Transplantation :... Jun 2024Magnesium (Mg2+) is essential for energy metabolism, muscle contraction, and neurotransmission. As part of the Mg-ATP complex, it is involved in over 600 enzymatic...
Magnesium (Mg2+) is essential for energy metabolism, muscle contraction, and neurotransmission. As part of the Mg-ATP complex, it is involved in over 600 enzymatic reactions. Serum Mg2+ levels are tightly regulated between 0.7 mmol/L and 1.1 mmol/L by interplay of intestinal absorption and renal excretion. In the small intestine, Mg2+ is absorbed paracellularly via claudin-2, and -12. In the colon, transcellular absorption of Mg2+ is facilitated by TRPM6/7 and CNNM4. In the kidney, the proximal tubule reabsorbs only 20% of the filtered Mg2+. The majority of the filtered Mg2+ is reabsorbed in the thick ascending limb (TAL), where the lumen-positive transepithelial voltage drives paracellular transport via claudin-16/-19. Fine-tuning of Mg2+ reabsorption is achieved in the distal convoluted tubule (DCT). Here, TRPM6/7 tetramers facilitate apical Mg2+ uptake, which is hormonally regulated by insulin and EGF. Basolateral Mg2+ extrusion is Na+ dependent and achieved by CNNM2 and/or SLC41A3. Hypomagnesemia (serum Mg2+ < 0.7 mmol/L) develops when intestinal and/or renal Mg2+ (re)absorption is disturbed. Common causes include alcoholism, type 2 diabetes mellitus, and the use of pharmacological drugs, such as proton-pump inhibitors (PPIs), calcineurin inhibitors (CNIs) and thiazide diuretics. Over the last decade, research on rare genetic and acquired Mg2+ disorders have identified Mg2+ channel and transporter activity, DCT length, mitochondrial function, and autoimmunity as mechanisms explaining hypomagnesemia. Classically, treatment of hypomagnesemia depended on oral or intravenous Mg2+ supplementation. Recently, prebiotic dietary fibers and SGLT2 inhibitors have been proposed as promising new therapeutic pathways to treat hypomagnesemia.
PubMed: 38871680
DOI: 10.1093/ndt/gfae134 -
Scientific Reports Jun 2024Early kidney injury may be detected by urinary markers, such as beta-2 microglobulin (B2M), tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth...
Early kidney injury may be detected by urinary markers, such as beta-2 microglobulin (B2M), tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7), kidney injury molecule-1 (KIM-1) and/or neutrophil gelatinase-associated lipocalin (NGAL). Of these biomarkers information on pathophysiology and reference ranges in both healthy and diseased populations are scarce. Differences in urinary levels of B2M, TIMP-2, IGFBP7, KIM-1 and NGAL were compared 24 h before and after nephrectomy in 38 living kidney donors from the REnal Protection Against Ischaemia-Reperfusion in transplantation study. Linear regression was used to assess the relation between baseline biomarker concentration and kidney function 1 year after nephrectomy. Median levels of urinary creatinine and creatinine standardized B2M, TIMP-2, IGFBP7, KIM-1, NGAL, and albumin 24 h before nephrectomy in donors were 9.4 mmol/L, 14 μg/mmol, 16 pmol/mmol, 99 pmol/mmol, 63 ng/mmol, 1390 ng/mmol and 0.7 mg/mmol, with median differences 24 h after nephrectomy of - 0.9, + 1906, - 7.1, - 38.3, - 6.9, + 2378 and + 1.2, respectively. The change of donor eGFR after 12 months per SD increment at baseline of B2M, TIMP-2, IGFBP7, KIM-1 and NGAL was: - 1.1, - 2.3, - 0.7, - 1.6 and - 2.8, respectively. Urinary TIMP-2 and IGFBP7 excretion halved after nephrectomy, similar to urinary creatinine, suggesting these markers predominantly reflect glomerular filtration. B2M and NGAL excretion increased significantly, similar to albumin, indicating decreased proximal tubular reabsorption following nephrectomy. KIM-1 did not change considerably after nephrectomy. Even though none of these biomarkers showed a strong relation with long-term donor eGFR, these results provide valuable insight into the pathophysiology of these urinary biomarkers.
Topics: Humans; Nephrectomy; Tissue Inhibitor of Metalloproteinase-2; beta 2-Microglobulin; Male; Female; Middle Aged; Insulin-Like Growth Factor Binding Proteins; Adult; Biomarkers; Kidney Transplantation; Living Donors; Kidney; Hepatitis A Virus Cellular Receptor 1; Creatinine; Lipocalin-2
PubMed: 38839764
DOI: 10.1038/s41598-024-62246-1 -
Kidney Diseases (Basel, Switzerland) Jun 2024G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular...
INTRODUCTION
G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular signaling pathways after interacting with bile acids. TGR5 plays an important role in multiple physiological processes and is considered to be a potential target for the treatment of various metabolic diseases, including type 2 diabetes. Evidence has emerged that genetic deletion of TGR5 results in an increase in basal urine output, suggesting that it may play a critical role in renal water and salt reabsorption. The present study aims to elucidate the effect and mechanism of TGR5 activation on urine concentration.
METHODS
Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days. The 24-h urine of mice was collected and analyzed for urine biochemical parameters. The mRNA expressions were detected by real-time PCR, and the protein expressions were detected by western blot. Immunohistochemistry and immunofluorescence were performed to examine the cellular location of proteins. The cultured primary medullary collecting duct cells were pretreated with H89 (a PKA inhibitor) for 1 h, followed by 12-h treatment of LCA and INT-777. Luciferase reporter assays were used to detect the effect of CREB on the gene transcription of AQPs. Gel electrophoretic mobility shift assays were used to analyze DNA-protein interactions.
RESULTS
Treatment of mice with the TGR5 agonist LCA and INT-777 markedly reduced urine output and increased urine osmolality, accompanied by a marked increase in AQP2 and AQP3 protein expression and membrane translocation. In cultured primary medullary collecting duct cells, LCA and INT-777 dose-dependently upregulated AQP2 and AQP3 expression in a cAMP/PKA-dependent manner. Mechanistically, both AQP2 and AQP3 gene promoter contains a putative CREB-binding site, which can be bound and activated by CREB as assessed by both gene promoter-driven luciferase and gel shift assays.
CONCLUSION
Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect.
PubMed: 38835402
DOI: 10.1159/000538107 -
Yakugaku Zasshi : Journal of the... 2024Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia,... (Review)
Review
Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.
Topics: Humans; Hyperuricemia; Uric Acid; ATP Binding Cassette Transporter, Subfamily G, Member 2; Organic Anion Transporters; Glucose Transport Proteins, Facilitative; Neoplasm Proteins; Xanthine Dehydrogenase; Animals; Organic Cation Transport Proteins; Renal Tubular Transport, Inborn Errors; Urinary Calculi; Metabolism, Inborn Errors
PubMed: 38825475
DOI: 10.1248/yakushi.23-00217 -
American Journal of Hypertension May 2024Renal proximal tubule plays a pivotal role in regulating sodium reabsorption and thus blood pressure. Transient receptor potential ankyrin 1 (TRPA1) has been reported to...
BACKGROUND
Renal proximal tubule plays a pivotal role in regulating sodium reabsorption and thus blood pressure. Transient receptor potential ankyrin 1 (TRPA1) has been reported to protect against renal injury by modulating mitochondrial function. We hypothesize that the activation of TRPA1 by its agonist cinnamaldehyde may mitigates high salt intake induced hypertension by inhibiting urinary sodium reabsorption through restoration of renal tubular epithelial mitochondrial function.
METHODS
Trpa1-deficient (Trpa1-/-) mice and wild-type (WT) mice were fed standard laboratory chow [normal diet (ND) group, 0.4% salt], standard laboratory chow with 8% salt [high-salt diet (HS) group] or standard laboratory chow with 8% salt plus 0.015% cinnamaldehyde [high-salt plus cinnamaldehyde diet (HSC) group] for six months. Urinary sodium excretion, ROS production, mitochondrial function and the expression of NHE3 and Na+/K+-ATPase of renal proximal tubules were determined.
RESULTS
Chronic dietary cinnamaldehyde supplementation reduced tail systolic blood pressure and 24-hour ambulatory arterial pressure in HS-fed WT mice. Compared with the mice fed HS, cinnamaldehyde supplementation significantly increased urinary sodium excretion, inhibited excess ROS production and alleviated mitochondrial dysfunction of renal proximal tubules in WT mice. However, these effects of cinnamaldehyde were absent in Trpa1-/- mice. Furthermore, chronic dietary cinnamaldehyde supplementation blunted HS-induced upregulation of NHE3 and Na+/K+-ATPase in WT mice but not Trpa1-/- mice.
CONCLUSION
The present study demonstrated that chronic activation of Trpa1 attenuates HS-induced hypertension by inhibiting urinary sodium reabsorption through restoring renal tubular epithelial mitochondrial function. Renal TRPA1 may be a potential target for the management of excessive dietary salt intake-associated hypertension.
PubMed: 38820173
DOI: 10.1093/ajh/hpae068 -
Journal of the Pediatric Infectious... May 2024Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone...
BACKGROUND
Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown.
METHODS
The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure.
RESULTS
Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers.
CONCLUSIONS
Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.
PubMed: 38820092
DOI: 10.1093/jpids/piae054 -
American Journal of Physiology. Renal... May 2024Hypertension affects approximately 1 in 2 US adults and sex plays an important role in the pathogenesis of hypertension. The sodium chloride cotransporter (NCC),...
Hypertension affects approximately 1 in 2 US adults and sex plays an important role in the pathogenesis of hypertension. The sodium chloride cotransporter (NCC), regulated by a kinase network including with-no-lysine kinases (WNK) 1 and WNK4, STE20/SPS1-related proline alanine rich kinase (SPAK), and oxidative stress response 1 (OxSR1) is critical to sodium reabsorption and blood pressure regulation. Dietary salt differentially modulates the NCC in salt-sensitive and salt-resistant rats, in part by modulation of WNK/SPAK/OxSR1 signaling. In these studies, we tested the hypothesis that sex-dependent differences in NCC regulation contribute to the development of the salt sensitivity of blood pressure using male and female Sprague Dawley, Dahl salt-resistant (DSR), and Dahl salt-sensitive (DSS) rats. In normotensive salt resistant SD and DSR rats a high salt diet evoked significant decreases in NCC activity, expression, and phosphorylation. In males these changes were associated with no change in WNK1 expression and a decrease in WNK4 levels and suppression of SPAK/OxSR1 expression and phosphorylation. In contrast in females decreased NCC activity associated with suppression of SPAK/OxSR1 expression and phosphorylation. In hypertensive DSS rats the ability of females to suppress NCC (in opposition to males) via a SPAK/OxSR1 mechanism likely contributes to their lower magnitude of salt-sensitive hypertension. Collectively our findings support the existence of sex differences in male versus female rats with NCC regulation during dietary salt intake involving suppression of WNK4 expression in male rats only and the involvement of SPAK/OxSR1 signaling in both males and females.
PubMed: 38813592
DOI: 10.1152/ajprenal.00150.2023 -
TouchREVIEWS in Endocrinology Apr 2024Type 2 diabetes (T2D) is one of the leading causes of morbidity and mortality worldwide. Currently, over 10.5% of the adult population has been diagnosed with T2D, and... (Review)
Review
Type 2 diabetes (T2D) is one of the leading causes of morbidity and mortality worldwide. Currently, over 10.5% of the adult population has been diagnosed with T2D, and almost 12% of total health expenditure is spent exclusively on T2D management globally. Sodium-glucose cotransporter-2 inhibitors are a relatively new class of oral antidiabetic agents that act by inhibiting renal sodium and glucose reabsorption. Except for their glucose-l owering effects, they have been associated with a more significant weight loss and blood pressure reduction and a lower risk of hypoglycaemia than other commonly prescribed antidiabetic drugs. On 20 January 2023, bexagliflozin became the fifth orally administered sodium-glucose transporter 2 inhibitor to be approved by the US Food and Drug Administration for the treatment of T2D as an adjunct therapy to diet and exercise in the USA after dapagliflozin, canagliflozin, empagliflozin and ertugliflozin. This review aims to discuss the current evidence on the efficacy and safety of bexagliflozin, which provides an important alternative treatment option for patients with T2D.
PubMed: 38812664
DOI: 10.17925/EE.2024.20.1.6