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International Journal of Molecular... Dec 2023Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium-phosphate cotransporters. Germline mutations in genes encoding these...
Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium-phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported a 33-year-old male patient presenting a history of recurrent nephrolithiasis and early onset osteopenia in the lumbar spine and femur. He was tested, through next generation sequencing (NGS), by using a customized multigenic panel containing 33 genes, whose mutations are known to be responsible for the development of congenital parathyroid diseases. Two further genes, and , encoding two sodium-phosphate cotransporters, were additionally tested. A novel germline heterozygous mutation was identified in the gene, c.1627G>T (p.Gly543Cys), currently not reported in databases of human gene mutations and scientific literature. germline heterozygous mutations have been associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1). Consistently, alongside the clinical features of NPHLOP1, our patient experienced recurrent nephrolithiasis and lumbar and femoral osteopenia at a young age. Genetic screening for the p.Gly453Cys variant and the clinical characterization of his first-degree relatives associated the presence of the variant in one younger brother, presenting renal colic and microlithiasis, suggesting p.Gly453Cys is possibly associated with renal altered function in the NPHLOP1 phenotype.
Topics: Humans; Male; Adult; Nephrolithiasis; Osteoporosis; Familial Hypophosphatemic Rickets; Mutation; Phosphates; Sodium-Phosphate Cotransporter Proteins; Sodium; Sodium-Phosphate Cotransporter Proteins, Type IIa
PubMed: 38139117
DOI: 10.3390/ijms242417289 -
Current Issues in Molecular Biology Nov 2023Clear cell renal cell carcinoma (ccRCC) is the most frequent form of kidney cancer. Metastatic stages of ccRCC reduce the five-year survival rate to 15%. In this report,...
Clear cell renal cell carcinoma (ccRCC) is the most frequent form of kidney cancer. Metastatic stages of ccRCC reduce the five-year survival rate to 15%. In this report, we analyze the ccRCC-induced remodeling of the five KEGG-constructed excretory functional pathways in a surgically removed right kidney and its metastasis in the chest wall from the perspective of the Genomic Fabric Paradigm (GFP). The GFP characterizes every single gene in each region by these independent variables: the average expression level (AVE), relative expression variability (REV), and expression correlation (COR) with each other gene. While the traditional approach is limited to only AVE analysis, the novel REV analysis identifies the genes whose correct expression level is critical for cell survival and proliferation. The COR analysis determines the real gene networks responsible for functional pathways. The analyses covered the pathways for aldosterone-regulated sodium reabsorption, collecting duct acid secretion, endocrine and other factor-regulated sodium reabsorption, proximal tubule bicarbonate reclamation, and vasopressin-regulated water reabsorption. The present study confirms the conclusion of our previously published articles on prostate and kidney cancers that even equally graded cancer nodules from the same tumor have different transcriptomic topologies. Therefore, the personalization of anti-cancer therapy should go beyond the individual, to his/her major cancer nodules.
PubMed: 38132440
DOI: 10.3390/cimb45120594 -
BMC Nephrology Dec 2023Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional... (Review)
Review
BACKGROUND
Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene.
CASE PRESENTATION
A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 μmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene.
CONCLUSIONS
This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.
Topics: Male; Humans; Adult; Posterior Leukoencephalopathy Syndrome; Glucose Transport Proteins, Facilitative; Acute Kidney Injury; Heterozygote; Mutation; Uric Acid; Organic Anion Transporters; Organic Cation Transport Proteins
PubMed: 38129773
DOI: 10.1186/s12882-023-03378-w -
Current Research in Toxicology 2024Urinary cadmium excretion (E) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular...
BACKGROUND
Urinary cadmium excretion (E) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β-microglobulinuria (E) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E) to E in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.
METHODS
To depict excretion rates per functional nephron, E, E, and E were normalized to creatinine clearance (C), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E/C, E/C, and eGFR to several independent variables. Simple linear regressions of eGFR, E/C, and E/C on E/C were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E/C and E/C and decrements in eGFR were quantified through four quartiles of E/C.
RESULTS
As age or E/C rose, E/C and E/C also rose, and eGFR fell. In linear regressions, slopes relating E/C and E/C to E/C were similar. After adjustment of dependent variables for age, coefficients of determination (R) for all regressions rose by a multiple, and slopes approached unity. E/C and E/C were similarly associated with each other. Mean E/C and E/C rose and mean eGFR fell in stepwise fashion through quartiles of E/C. Whereas E/C did not vary with blood pressure, E/C rose in association with hypertension in two of the four quartiles.
CONCLUSIONS
Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and βM similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.
PubMed: 38116328
DOI: 10.1016/j.crtox.2023.100140 -
BMC Nephrology Dec 2023Chronic renal failure (CRF) is defined by a significant decline in renal function that results in decreased salt filtration and inhibition of tubular reabsorption, which...
BACKGROUND
Chronic renal failure (CRF) is defined by a significant decline in renal function that results in decreased salt filtration and inhibition of tubular reabsorption, which ultimately causes volume enlargement. This study evaluated the potential renopreventive effects of the NLRP3 inflammasome inhibitor MCC950 in adenine-induced CRF in rats due to conflicting evidence on the effects of MCC950 on the kidney.
METHODS
Since the majority of the kidney tubular abnormalities identified in people with chronic renal disease are comparable to those caused by adding 0.75 percent of adenine powder to a rat's diet each day for four weeks, this method has received broad approval as a model for evaluating kidney damage. Throughout the test, blood pressure was checked weekly and at the beginning. Additionally, oxidative stress factors, urine sample examination, histological modifications, and immunohistochemical adjustments of caspase-3 and interleukin-1 beta (IL-1) levels in renal tissues were carried out.
RESULTS
Results revealed that MCC950, an inhibitor of the NLRP3 inflammasome, had a renopreventive effect, which was demonstrated by a reduction in blood pressure readings and an improvement in urine, serum, and renal tissue indicators that indicate organ damage. This was also demonstrated by the decrease in neutrophil gelatinase-associated lipocalin tubular expression (NGAL). The NLRP3 inflammasome inhibitor MCC950 was found to significantly alleviate the worsening renal cellular alterations evidenced by increased expression of caspase-3 and IL-1, according to immunohistochemical tests.
CONCLUSION
The NLRP3 inflammasome inhibitor MCC950 demonstrated renopreventive effects in the CRF rat model, suggesting that it might be used as a treatment strategy to stop the progression of CRF.
Topics: Humans; Rats; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Caspase 3; Sulfones; Sulfonamides; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Interleukin-1; Furans; Disease Models, Animal
PubMed: 38114914
DOI: 10.1186/s12882-023-03427-4 -
European Journal of Nuclear Medicine... Apr 2024Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli,...
PURPOSE
Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity.
METHODS
A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [Pb]Pb-MC1L, was used for [Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers.
RESULTS
Biodistribution analysis identified [Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings.
CONCLUSION
Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.
Topics: Mice; Animals; Lipocalin-2; Lead; Tissue Distribution; Early Detection of Cancer; Biomarkers; Renal Insufficiency, Chronic; Creatinine
PubMed: 38095674
DOI: 10.1007/s00259-023-06559-9 -
European Journal of Case Reports in... 2023Familial renal glucosuria (FRG) is a rare genetic disease characterised by isolated glucosuria in the absence of proximal tubular dysfunction. It usually occurs due to a...
UNLABELLED
Familial renal glucosuria (FRG) is a rare genetic disease characterised by isolated glucosuria in the absence of proximal tubular dysfunction. It usually occurs due to a mutation in the gene encoding the sodium-glucose cotransporter-2 (SGLT2), responsible for most of the renal glucose reabsorption. We report on a case of a patient presenting with paroxysmal glucosuria and hypercalciuria due to a novel heterozygous variant.
LEARNING POINTS
FRG usually presents with glucosuria but may also be associated with hypercalciuria and aminoaciduria.The amount of glucosuria is variable and can be normal in the same FRG patient because it is influenced by different glycaemia levels. This raises the question of whether the definition of FRG should be broadened to paroxysmal glucosuria.Having glucosuria does not prevent the development of insulin resistance.
PubMed: 38077699
DOI: 10.12890/2023_004157 -
Nutrients Nov 2023Abnormal lipid metabolism increases the relative risk of kidney disease in patients with a single kidney. Using transcriptome analysis, we investigated whether a...
Abnormal lipid metabolism increases the relative risk of kidney disease in patients with a single kidney. Using transcriptome analysis, we investigated whether a high-fat diet leads to abnormalities in lipid metabolism and induces kidney cell-specific damage in unilateral nephrectomy mice. Mice with unilateral nephrectomy fed a high-fat diet for 12 weeks exhibited progressive renal dysfunction in proximal tubules, including lipid accumulation, vacuolization, and cell damage. Ring finger protein 20 (RNF20) is a ligase of nuclear receptor corepressor of peroxisome proliferator-activated receptors (PPARs). The transcriptome analysis revealed the involvement of RNF20-related transcriptome changes in PPAR signaling, lipid metabolism, and water transmembrane transporter under a high-fat diet and unilateral nephrectomy. In vitro treatment of proximal tubular cells with palmitic acid induced lipotoxicity by altering RNF20, PPARα, and ATP-binding cassette subfamily A member 1 (ABCA1) expression. PPARγ and aquaporin 2 (AQP2) expression decreased in collecting duct cells, regulating genetic changes in the water reabsorption process. In conclusion, a high-fat diet induces lipid accumulation under unilateral nephrectomy via altering RNF20-mediated regulation and causing functional damage to cells as a result of abnormal lipid metabolism, thereby leading to structural and functional kidney deterioration.
Topics: Animals; Mice; Aquaporin 2; Diet, High-Fat; Kidney; Kidney Diseases; Lipid Metabolism; Lipids; Nephrectomy; PPAR alpha; Ubiquitin-Protein Ligases; Water
PubMed: 38068817
DOI: 10.3390/nu15234959 -
Nature Structural & Molecular Biology Jan 2024Sodium-glucose cotransporter 2 (SGLT2) is imporant in glucose reabsorption. SGLT2 inhibitors suppress renal glucose reabsorption, therefore reducing blood glucose levels...
Sodium-glucose cotransporter 2 (SGLT2) is imporant in glucose reabsorption. SGLT2 inhibitors suppress renal glucose reabsorption, therefore reducing blood glucose levels in patients with type 2 diabetes. We and others have developed several SGLT2 inhibitors starting from phlorizin, a natural product. Using cryo-electron microscopy, we present the structures of human (h)SGLT2-MAP17 complexed with five natural or synthetic inhibitors. The four synthetic inhibitors (including canagliflozin) bind the transporter in the outward conformations, while phlorizin binds it in the inward conformation. The phlorizin-hSGLT2 interaction exhibits biphasic kinetics, suggesting that phlorizin alternately binds to the extracellular and intracellular sides. The Na-bound outward-facing and unbound inward-open structures of hSGLT2-MAP17 suggest that the MAP17-associated bundle domain functions as a scaffold, with the hash domain rotating around the Na-binding site. Thus, Na binding stabilizes the outward-facing conformation, and its release promotes state transition to inward-open conformation, exhibiting a role of Na in symport mechanism. These results provide structural evidence for the Na-coupled alternating-access mechanism proposed for the transporter family.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Glucose Transporter 2; Diabetes Mellitus, Type 2; Glucose Transport Proteins, Facilitative; Phlorhizin; Cryoelectron Microscopy; Glucose
PubMed: 38057552
DOI: 10.1038/s41594-023-01134-0 -
Molecular Metabolism Jan 2024Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism...
OBJECTIVE
Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity.
METHODS
We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI.
RESULTS
MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival.
CONCLUSIONS
Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.
Topics: Mice; Animals; Monocarboxylic Acid Transporters; Acute Kidney Injury; Oxidation-Reduction; Rhabdomyolysis; Oxidants
PubMed: 38056691
DOI: 10.1016/j.molmet.2023.101849