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Biomedicines Apr 2023Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular... (Review)
Review
Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress.
PubMed: 37238929
DOI: 10.3390/biomedicines11051258 -
IScience Dec 2022Our recent study has found that gut bacteria contributes to hypertension and upregulates lysophospholipase A1 (LYPLA1) in the renal medulla of rats. This work aimed to...
Our recent study has found that gut bacteria contributes to hypertension and upregulates lysophospholipase A1 (LYPLA1) in the renal medulla of rats. This work aimed to investigate the role of LYPLA1 in the development of -induced hypertension. Compared to control, treatment increased blood pressure (BP), serum angiotensin II, sodium reabsorption, and expression of αENaC and LYPLA1 in the renal medulla of mice, and these effects were attenuated by knockdown of LYPLA1. Moreover, the intrarenal overexpression increased sodium reabsorption and BP. Further studies showed that LYPLA1 promoted the accumulation of renal glycerophosphocholine (GPC), which directly elevated the expression of αENaC and sodium reabsorption. In addition, enriched abundance of LYPLA1 in the renal medulla and urine was also observed in other hypertensive animals. Overall, our results demonstrate that LYPLA1 contributes to -induced hypertension by accumulating GPC and activating ENaC in the renal medulla.
PubMed: 36419851
DOI: 10.1016/j.isci.2022.105403 -
Porto Biomedical Journal 2021The kidneys play an important role in maintaining glucose homeostasis being the main mechanisms, the gluconeogenesis, renal glucose consumption and glucose reabsorption... (Review)
Review
The kidneys play an important role in maintaining glucose homeostasis being the main mechanisms, the gluconeogenesis, renal glucose consumption and glucose reabsorption in the proximal tubules. In this review, we present the main research into the role of glycogen-the stored form of glucose, and how it accumulates in the cells, providing new information on the link between diabetes and diabetic kidney disease. In the last 10 years, research under the scope of renal insulin handling, glucose transport in the proximal tubules, renal gluconeogenesis and renal insulin resistance, made possible to relate the roles of glucose and glycogen in the kidney with other several organs, like the liver. On the one hand, insulin positively regulates kidney uptake and degradation, and there is probably a specific action and resistance to insulin at the renal site. Moreover, insulin regulates the bioavailability of the sodium-glucose co-transporters-SGLT2 inhibitor, and inhibits renal gluconeogenesis. Only the liver and kidneys can supply glucose to the circulation through the process of gluconeogenesis, which involves the synthesis of glucose again from non-glycemic substrates; and the decomposition of stored glycogen. In the mind of nephrologists, diabetologists and scientists, glucose metabolism in the kidney is the focus, with the relevant success of inhibitors in reducing kidney and cardiovascular diseases in individuals with diabetes. However, these new data led to the intriguing paradigm that many of the beneficial effects on the renal and cardiovascular system appear to be independent of the systemic glucose-lowering actions of these agents. The goal of this work puts in context a highly relevant research area for renal glucose metabolism, of glycogen accumulation and metabolism in the diabetic kidney.
PubMed: 33532655
DOI: 10.1097/j.pbj.0000000000000113 -
American Journal of Physiology. Renal... Jan 2021Sexual dimorphic variations are present in many aspects of biology and involve the structure and/or function of nearly every organ system. Acid-base homeostasis is...
Sexual dimorphic variations are present in many aspects of biology and involve the structure and/or function of nearly every organ system. Acid-base homeostasis is critical for optimal health, and renal ammonia metabolism has a major role in the maintenance of acid-base homeostasis. Recent studies have shown sex-dependent differences in renal ammonia metabolism with regard to both basal ammonia excretion and the response to an exogenous acid load. These sexual dimorphisms are associated with structural changes in the proximal tubule and the collecting duct and variations in the expression of multiple proteins involved in ammonia metabolism and transport. Studies using orchiectomy-induced testosterone deficiency and physiological testosterone replacement have shown that testosterone underlies much of the sex-dependent differences in the proximal tubule. This parallels the finding that the canonical testosterone target receptor, androgen receptor (AR), is present exclusively in the proximal tubule. Thus testosterone, possibly acting through AR activation, regulates multiple components of renal structure and ammonia metabolism. The lack of detectable AR in the remainder of the nephron and collecting duct suggests that some dimorphisms in renal structure and ammonia transporter expression are mediated through mechanisms other than direct testosterone-dependent AR activation. A better understanding of the mechanism and biological implications of sex's effect on renal structure and ammonia metabolism is critical for optimizing our ability to care for both men and women with acid-base disturbances.
Topics: Acid-Base Equilibrium; Ammonia; Animals; Female; Humans; Hydrogen-Ion Concentration; Kidney Tubules, Proximal; Male; Membrane Transport Proteins; Receptors, Androgen; Renal Elimination; Renal Reabsorption; Sex Characteristics; Sex Factors; Testosterone
PubMed: 33308019
DOI: 10.1152/ajprenal.00531.2020 -
International Journal of Molecular... Jan 2023Farnesoid X receptor, also known as the bile acid receptor, belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors, which performs... (Review)
Review
Farnesoid X receptor, also known as the bile acid receptor, belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors, which performs its functions by regulating the transcription of target genes. FXR is highly expressed in the liver, small intestine, kidney and adrenal gland, maintaining homeostasis of bile acid, glucose and lipids by regulating a diverse array of target genes. It also participates in several pathophysiological processes, such as inflammation, immune responses and fibrosis. The kidney is a key organ that manages water and solute homeostasis for the whole body, and kidney injury or dysfunction is associated with high morbidity and mortality. In the kidney, FXR plays an important role in renal water reabsorption and is thought to perform protective functions in acute kidney disease and chronic kidney disease, especially diabetic kidney disease. In this review, we summarize the recent advances in the understanding of the physiological and pathophysiological function of FXR in the kidney.
Topics: Humans; Bile Acids and Salts; Diabetic Nephropathies; Kidney; Liver; Transcription Factors; Fragile X Mental Retardation Protein
PubMed: 36768731
DOI: 10.3390/ijms24032408 -
Nature Communications Jun 2023Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice,...
Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans.
Topics: Humans; Mice; Animals; Nucleosides; Membrane Transport Proteins; Pyrimidine Nucleosides; Renal Elimination; Carrier Proteins; Antimetabolites; Nucleoside Transport Proteins; Kidney
PubMed: 37264059
DOI: 10.1038/s41467-023-38789-8 -
Biochemical Society Transactions Feb 2022Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with... (Review)
Review
Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral Pi binder and dietary Pi restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma Pi levels. In addition, a paradoxical increase in expression of intestinal Pi transporter and uptake may occur. Recently, studies in rodents targeting the renal Na+/Pi cotransporter 2a (Npt2a), responsible for ∼70% of Pi reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary Pi excretion consequently lowering plasma Pi and PTH levels. Additionally, increases in urinary excretions of Na+, Cl- and Ca2+ have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on Pi homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.
Topics: Animals; Female; Humans; Hyperphosphatemia; Male; Mice; Mice, Knockout; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Sodium-Phosphate Cotransporter Proteins, Type IIa
PubMed: 34994388
DOI: 10.1042/BST20211005 -
Nutrients Aug 2020Vitamin D is well known for its important roles in maintaining calcium homeostasis and bone mineralization via the regulation of calcium mobilization and renal...
Vitamin D is well known for its important roles in maintaining calcium homeostasis and bone mineralization via the regulation of calcium mobilization and renal reabsorption, and the intestinal absorption of both calcium and phosphorus [...].
Topics: Bone and Bones; Calcification, Physiologic; Calcium; Epigenesis, Genetic; Homeostasis; Humans; Intestinal Absorption; Nutrigenomics; Nutritional Physiological Phenomena; Receptors, Calcitriol; Renal Reabsorption; Vitamin D; Vitamin D Response Element
PubMed: 32785003
DOI: 10.3390/nu12082388 -
Biomedical Journal Feb 2022Magnesium (Mg) is an important intracellular cation and essential to maintain cell function including cell proliferation, immunity, cellular energy metabolism, protein... (Review)
Review
Magnesium (Mg) is an important intracellular cation and essential to maintain cell function including cell proliferation, immunity, cellular energy metabolism, protein and nucleic acid synthesis, and regulation of ion channels. Consequences of hypomagnesemia affecting multiple organs can be in overt or subtle presentations. Besides detailed history and complete physical examination, the assessment of urinary Mg excretion is help to differentiate renal from extra-renal (gastrointestinal, tissue sequestration, and shifting) causes of hypomagnesemia. Renal hypomagnesemia can be caused by an increased glomerular filtration and impaired reabsorption in proximal tubular cells, thick ascending limb of the loop of Henle or distal convoluted tubules. A combination of renal Mg wasting, familial history, age of onset, associated features, and exclusion of acquired etiologies point to inherited forms of renal hypomagnesemia. Based on clinical phenotypes, its definite genetic diagnosis can be simply grouped into specific, uncertain, and unknown gene mutations with a priority of genetic approach methods. An unequivocal molecular diagnosis could allow for prediction of clinical outcome, providing genetic counseling, avoiding unnecessary studies or interventions, and possibly uncovering the pathogenic mechanism. Given numerous identified genes responsible for Mg transport in renal hypomagnesemia over the past two decades, several potential and specific molecular and cellular therapeutic strategies to correct hypomagnesemia are promising.
Topics: Humans; Kidney Tubules, Distal; Magnesium; Phenotype
PubMed: 34767995
DOI: 10.1016/j.bj.2021.11.002 -
Journal of Clinical Medicine Aug 2021Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free... (Review)
Review
Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as "cast nephropathy". Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment.
PubMed: 34501317
DOI: 10.3390/jcm10173871