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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 -
Molecular Biotechnology Mar 2024This study focused on identifying potential key lncRNAs associated with gout under the mechanisms of copper death and iron death through ceRNA network analysis and...
This study focused on identifying potential key lncRNAs associated with gout under the mechanisms of copper death and iron death through ceRNA network analysis and Random Forest (RF) algorithm, which aimed to provide new insights into the molecular mechanisms of gout, and potential molecular targets for future therapeutic strategies of gout. Initially, we conducted an in-depth bioinformatics analysis of gout microarray chips to screen the key cuproptosis-related genes (CRGs) and key ferroptosis-related genes (FRGs). Using these data, we constructed a key ceRNA network for gout. Finally, key lncRNAs associated with gout were identified through the RF algorithm combined with ROC curves, and validated using the Comparative Toxicogenomics Database (CTD). We successfully identified NLRP3, LIPT1, and DBT as key CRGs associated with gout, and G6PD, PRKAA1, LIG3, PHF21A, KLF2, PGRMC1, JUN, PANX2, and AR as key FRGs associated with gout. The key ceRNA network identified four downregulated key lncRNAs (SEPSECS-AS1, LINC01054, REV3L-IT1, and ZNF883) along with three downregulated mRNAs (DBT, AR, and PRKAA1) based on the ceRNA theory. According to CTD validation inference scores and biological functions of target mRNAs, we identified a potential gout-associated lncRNA ZNF883/hsa-miR-539-5p/PRKAA1 regulatory axis. This study identified the key lncRNA ZNF883 in the context of copper death and iron death mechanisms related to gout for the first time through the application of ceRNA network analysis and the RF algorithm, thereby filling a research gap in this field and providing new insights into the molecular mechanisms of gout. We further found that lncRNA ZNF883 might function in gout patients by regulating PRKAA1, the mechanism of which was potentially related to uric acid reabsorption in the proximal renal tubules and inflammation regulation. The proposed lncRNA ZNF883/hsa-miR-539-5p/PRKAA1 regulatory axis might represent a potential RNA regulatory pathway for controlling the progression of gout disease. This discovery offered new molecular targets for the treatment of gout, and had significant implications for future therapeutic strategies in managing the gout.
PubMed: 38472694
DOI: 10.1007/s12033-024-01099-5 -
American Journal of Physiology.... May 2024Potassium (K) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation,...
Potassium (K) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, and hormone secretion and action. Indeed, maintaining K balance is critical for normal cell function, as too high or too low K levels can have serious and potentially deadly health consequences. K homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na-K-ATPase uptake, and hormone and electrolyte impacts on renal K handling. We recently developed a mathematical model of whole body K regulation to unravel the individual impacts of these regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high-K diet. We conducted model simulations and sensitivity analyses to investigate how these renal alterations impact whole body K regulation. Model predictions quantify the sensitivity of K regulation to various levels of proximal tubule K reabsorption adaptation and tubuloglomerular feedback. Our results suggest that the reduced proximal tubule K reabsorption under a high-K diet could achieve K balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K excretion. Potassium homeostasis is maintained in the body by a complex system of regulatory mechanisms. This system, when healthy, maintains a small extracellular potassium concentration, despite large fluctuations of dietary potassium. The complexities of the system make this problem well suited for investigation with mathematical modeling. In this study, we extend our mathematical model to consider recent experimental results on renal potassium handling on a high potassium diet and investigate the impacts from a whole body perspective.
Topics: Feedback; Kidney Tubules, Proximal; Electrolytes; Potassium; Hormones
PubMed: 38465401
DOI: 10.1152/ajpregu.00283.2023 -
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 -
Cardiovascular Research Apr 2024An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease... (Review)
Review
An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Animals; Treatment Outcome; Blood Glucose; Sodium-Glucose Transporter 2; Risk Assessment; Risk Factors; Cardiovascular System; Biomarkers
PubMed: 38456601
DOI: 10.1093/cvr/cvae047 -
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 -
Animal Biotechnology Nov 2024Milk urea (MU) concentration is proposed as an indicator trait for breeding toward reduced nitrogen (N) emissions and leaching in dairy. We selected 20 German Holstein...
Milk urea (MU) concentration is proposed as an indicator trait for breeding toward reduced nitrogen (N) emissions and leaching in dairy. We selected 20 German Holstein cows based on MU breeding values, with 10 cows each having low (LMUg) and high (HMUg) MU genetic predisposition. Using RNA-seq, we characterized these cows to unravel molecular pathways governing post-absorptive body N pools focusing on renal filtration and reabsorption of nitrogenous compounds, hepatic urea formation and mammary gland N excretion. While we observed minor adjustments in cellular energy metabolism in different tissues associated with different MU levels, no transcriptional differences in liver ammonia detoxification were detected, despite significant differences in MU between the groups. Differential expression of and in the kidney provides evidence for higher urea concentration in the collecting duct of LMU cows than HMU cows. The mammary gland exhibited the most significant differences, particularly in tricarboxylic acid (TCA) cycle genes, amino acid transport, tRNA binding, and casein synthesis. These findings suggest that selecting for lower MU could lead to altered urinary urea (UU) handling and changes in milk protein synthesis. However, given the genetic variability in N metabolism components, the long-term effectiveness of MU-based selection in reducing N emissions remains uncertain.
Topics: Female; Cattle; Animals; Lactation; Milk; Milk Proteins; Urea; RNA-Seq; Nitrogen; Diet
PubMed: 38426941
DOI: 10.1080/10495398.2024.2322542 -
BMJ Case Reports Feb 2024Magnesium is essential for the functioning and release of parathyroid hormone. Therefore, its deficiency can present as functional hypoparathyroidism. This case report...
Magnesium is essential for the functioning and release of parathyroid hormone. Therefore, its deficiency can present as functional hypoparathyroidism. This case report describes a rare inherited disorder called congenital hypomagnesaemia with secondary hypocalcaemia due to gene mutation. This disease clinically and biochemically mimics hypoparathyroidism. However, unlike hypoparathyroidism, it can be treated only by long-term oral magnesium supplements. The patient presented to us with recurrent hypocalcaemic convulsions. The laboratory picture in each admission was similar to that of hypoparathyroidism. However, the hypocalcaemia persisted, and it was noticed to be associated with persistent hypomagnesaemia. A defect in the tubular magnesium reabsorption was postulated and a genetic analysis of the patient was done, which revealed a mutation causing hypomagnesaemia by excessive renal excretion of magnesium. The child responded well to oral magnesium supplements and is currently developmentally appropriate for her age and thriving well.
Topics: Child; Female; Humans; Magnesium; Hypocalcemia; Hypoparathyroidism; Mutation; Magnesium Deficiency; TRPM Cation Channels
PubMed: 38413141
DOI: 10.1136/bcr-2023-257505