Uromodulin Research Articles

Značaj određivanja koncentracije uromodulina u serumu bolesnika sa dijabetes melitusom tip 2

Introduction: In the kidney, cells in the thick ascending limb of the loop of the Henle synthesized uromodulin (UMOD). This study aims to present the evaluation of the uromodulin serum concentration in diabetes mellitus type 2 (T2DM) patients in the early detection of kidney damage. Materials and methods: The study included 50 T2DM patients mean age of 60.75 ± 11.23 years estimated glomerular filtration rate (eGFR) 114.38 ± 22.12 ml/min and a control group of 20 healthy persons. We measured serum concentration of haemoglobin, urea, creatinine, uromodulin (ELISA method), and cystatin C (nephelometry). We determined formulas: Cockcroft-Gault# (combination Cockcroft-Gault for patients with BMI < 30 kg/m2 and Cockcroft-GaultLBW for patients with BMI ≥ 30 kg/m2), CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration equation), and simple Cystatin C. Results: T2DM patients had lower hemoglobin serum concentration as well as eGFR calculated by formulas: Cockcroft-Gault# and CKD-EPI. T2DM patients had significantly higher BMI and cystatin C compared to control group. T2DM patients had significantly lower serum uromodulin concentration (136.51 ± 84.34 vs 220.50 ± 92.39 ng/ml) than in controls. Significant positive correlation between uromodulin and Cockcroft-Gault# (r = 0.432, p = 0.000), CKD-EPI (r = 0.439; p = 0.000) formulas as well as simple cystatin C (r = 0.250, p = 0.02), but negative correlation with age (r = -0.476, p = 0.000), BMI (r = -0.313, p = 0.002) and cystatin C serum concentration (r = -0.293, p = 0.015) were found. Conclusion: The role of serum uromodulin concentration is not still fortified. The results of this study showed that reduced uromodulin serum concentration indicated early kidney damage in T2DM patients.

Study of Uromodulin Gene Polymorphism in Egyptian Patients with End-Stage Renal Disease.

Uromodulin (UMOD) gene polymorphism has been linked with end-stage renal disease. In this research, we studied the prevalence of UMOD rs42993393 T>C in Egyptian hemodialysis (HD) patients and the blood level of UMOD in those patients. The study was a case-control study and included 100 patients on regular HD and 100 healthy control subjects. The blood samples from the studied groups were subjected to the determination of UMOD blood level and molecular study of UMOD rs42993393 T>C genotype by polymerase chain reaction with restriction fragment length polymorphism. The serum UMOD level was significantly low in patients (38.6 7.6 ng/mL) compared to control subjects (221.3 ± 54.2, P = 0.0001). On the other hand, the UMOD rs42993393T>C was significantly increased in TC in patients (28%, odds ratio 1.3-1.0-2.0) compared to controls (22%, P = 0.03), and there was a significant increase in CC in patients (10%) compared to control subjects (3%; P = 0.0001). The T allele was significantly increased in controls compared to patients with a significant increase in C allele in patients compared to controls (P = 0.01). The present study highlights the prevalence of UMOD gene polymorphism at rs42993393T>C. There was a significant prevalence of C allele and C genotypes in HD patients. This finding may indicate that this allele may be a predisposing genotype for renal failure in susceptible patients. On the other hand, the significant reduction of serum UMOD in patients with end-stage renal disease may be attributed to the reduced functioning renal mass.

ASSOCIATION OF GENETIC POLYMORPHISM AND EXPRESSION OF UMOD GENE AND CHRONIC KIDNEY DISEASE

The aim: This study is designed to investigate the possible association of genetic polymorphism expression of UMOD gene and chronic kidney disease in population. Materials and methods: In the current study, the single-nucleotide polymorphisms (SNPs) were genotyped in the promoter region of the UMOD gene in CKD patients to assess its association with the kidney outcome of CKD. So 50 patients’ blood samples suffered from CKD were collected. Among these patients, 21 were men and 29 women, aged 35 – 85 years old. Another group included 50 healthy subjects. DNA was extracted from all blood samples with EDTA using Quick DNA miniprep Kit ZYMO, (Cat№ D3025) according to manufacturer’s instructions. Genotyping of 1 common polymorphisms (rs4293393) of the UMOD gene was done and the RNA was extracted and converted to cDNA and a set of primers was used to amplify specific region within the UMOD gene; another set was used to amplify the GAPDH gene to use it in calculation as a reference gene. Results and conclusions: After statistical analysis, the results showed that there could be association between having CC mutant polymorphism in UMOD gene and having CKD.

Acute kidney injury in a mouse model of meningococcal disease

IntroductionMeningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease.MethodsFemale BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice.ResultsIn the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte–macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm–Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect.ConclusionOur findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.

Application of tandem fast protein liquid chromatography to purify intact native monomeric/aggregated Tamm-Horsfall protein from human urine and systematic comparisons with diatomaceous earth adsorption and salt precipitation: yield, purity and time-consumption.

Tamm-Horsfall protein (THP) is a high-abundance urinary protein. Although its functions have been studied for years, several aspects of these remain unclear. To achieve more knowledge on THP functions, an effective isolation/purification method providing a high yield and high purity is required. This is the first report that applied tandem fast protein liquid chromatography (FPLC) (by combining Mono Q anion-exchange with Superdex 200 size-exclusion columns in a tandem manner) to isolate intact THP from human urine. Its efficiency was then systematically compared with that of two conventional methods, diatomaceous earth (DE) adsorption and salt precipitation. The first ever systematic comparisons among the three methods revealed that, while Mono Q-Superdex 200 tandem FPLC offered the lowest %yield and was most time-consuming, it provided substantially high %purity and could selectively purify the monomeric and aggregated forms of urinary THP. On the other hand, DE adsorption provided the highest %yield and %purity, whereas salt precipitation offered the lowest %purity. In summary, the tandem FPLC system is most useful for selective purification of the monomeric and aggregated forms of urinary THP for further functional study, whereas DE adsorption remains the method of choice for general purification of THP from human urine.

Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo.

Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.

Clinically Viable Assay for Monitoring Uromodulin Glycosylation.

Uromodulin, also known as the Tamm-Horsfall protein or THP, is the most abundant protein excreted in human urine. It is associated with the progression of kidney diseases; therefore, changes in the glycosylation profile of this protein could serve as a potential biomarker for kidney health. The typical glycomics analysis approaches used to quantify uromodulin glycosylation involve time-consuming and tedious glycoprotein isolation and labeling steps, which limit their utility in clinical glycomics assays, where sample throughput is important. Herein, we introduce a radically simplified sample preparation workflow, with direct ESI-MS analysis, enabling the quantification of N-linked glycans that originate from uromodulin. The method omits any glycan labeling steps but includes steps to reduce the salt content of the samples, thereby minimizing ion suppression. The method is effective for quantifying subtle glycosylation differences of uromodulin samples derived from different biological states. As a proof of concept, glycosylation from samples that differ by pregnancy status were shown to be differentiable.

Association of Non-Steroidal Anti-Inflammatory Drugs with Kidney Health in Ambulatory Older Adults.

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause kidney injury, especially in older adults. However, previously reported associations between NSAID use and kidney health outcomes are inconsistent and limited by reliance on serum creatinine-based GFR estimates. This analysis investigated the association of NSAID use with kidney damage in older adults using multiple kidney health measures. Cross-sectional and longitudinal analyses. Multicenter, community-based cohort. Two thousand nine hundred and ninty nine older adults in the Health ABC Study. A subcohort (n = 500) was randomly selected for additional biomarker measurements. Prescription and over-the-counter NSAID use ascertained by self-report. Baseline estimated glomerular filtration rate (eGFR) by cystatin C (cysC), urine albumin-to-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) were measured in 2,999 participants; alpha-1 microglobulin (α1m), neutrophil gelatinase-associated lipocalin (NGAL), propeptide type III procollagen (PIIINP), and uromodulin (UMOD) were measured in 500 participants. GFR was estimated three times over 10 years and expressed as percent change per year. Participants had a mean age of 74 years, 51% were female, and 41% African-American. No eGFR differences were detected between NSAID users (n = 655) and non-users (n = 2,344) at baseline (72 ml/min/1.73 m2 in both groups). Compared to non-users, NSAID users had lower adjusted odds of having ACR greater than 30 mg/g (0.67; 95% confidence interval (CI) = 0.51-0.89) and lower mean urine IL-18 concentration at baseline (-11%; 95% CI = -4% to -18%), but similar mean KIM-1 (5%; 95% CI = -5% to 14%). No significant differences in baseline concentrations of the remaining urine biomarkers were detected. NSAID users and non-users did not differ significantly in the rate of eGFR decline (-2.2% vs -2.3% per year). Self-reported NSAID use was not associated with kidney dysfunction or injury based on multiple measures, raising the possibility of NSAID use without kidney harm in ambulatory older adults. More research is needed to define safe patterns of NSAID consumption.

Cryo‐EM structure of native human uromodulin, a zona pellucida module polymer

Assembly of extracellular filaments and matrices mediating fundamental biological processes such as morphogenesis, hearing, fertilization, and antibacterial defense is driven by a ubiquitous polymerization module known as zona pellucida (ZP) “domain”. Despite the conservation of this element from hydra to humans, no detailed information is available on the filamentous conformation of any ZP module protein. Here, we report a cryo‐electron microscopy study of uromodulin (UMOD)/Tamm–Horsfall protein, the most abundant protein in human urine and an archetypal ZP module‐containing molecule, in its mature homopolymeric state. UMOD forms a one‐start helix with an unprecedented 180‐degree twist between subunits enfolded by interdomain linkers that have completely reorganized as a result of propeptide dissociation. Lateral interaction between filaments in the urine generates sheets exposing a checkerboard of binding sites to capture uropathogenic bacteria, and UMOD‐based models of heteromeric vertebrate egg coat filaments identify a common sperm‐binding region at the interface between subunits.

Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease.

Actin-associated nonmuscle myosin II (NM2) motor proteins play critical roles in a myriad of cellular functions, including endocytosis and organelle transport pathways. Cell type–specific expression and unique subcellular localization of the NM2 proteins, encoded by the Myh9 and Myh10 genes, in the mouse kidney tubules led us to hypothesize that these proteins have specialized functional roles within the renal epithelium. Inducible conditional knockout (cKO) of Myh9 and Myh10 in the renal tubules of adult mice resulted in progressive kidney disease. Prior to overt renal tubular injury, we observed intracellular accumulation of the glycosylphosphatidylinositol-anchored protein uromodulin (UMOD) and gradual loss of Na+ K+ 2Cl– cotransporter from the apical membrane of the thick ascending limb epithelia. The UMOD accumulation coincided with expansion of endoplasmic reticulum (ER) tubules and activation of ER stress and unfolded protein response pathways in Myh9&10-cKO kidneys. We conclude that NM2 proteins are required for localization and transport of UMOD and loss of function results in accumulation of UMOD and ER stress–mediated progressive renal tubulointerstitial disease. These observations establish cell type–specific role(s) for NM2 proteins in regulation of specialized renal epithelial transport pathways and reveal the possibility that human kidney disease associated with MYH9 mutations could be of renal epithelial origin.

NaCl cotransporter activity and Mg2+ handling by the distal convoluted tubule.

The genetic disease Gitelman syndrome, knockout mice, and pharmacological blockade with thiazide diuretics have revealed that reduced activity of the NaCl cotransporter (NCC) promotes renal Mg2+ wasting. NCC is expressed along the distal convoluted tubule (DCT), and its activity determines Mg2+ entry into DCT cells through transient receptor potential channel subfamily M member 6 (TRPM6). Several other genetic forms of hypomagnesemia lower the drive for Mg2+ entry by inhibiting activity of basolateral Na+-K+-ATPase, and reduced NCC activity may do the same. Lower intracellular Mg2+ may promote further Mg2+ loss by directly decreasing activity of Na+-K+-ATPase. Lower intracellular Mg2+ may also lower Na+-K+-ATPase indirectly by downregulating NCC. Lower NCC activity also induces atrophy of DCT cells, decreasing the available number of TRPM6 channels. Conversely, a mouse model with increased NCC activity was recently shown to display normal Mg2+ handling. Moreover, recent studies have identified calcineurin and uromodulin (UMOD) as regulators of both NCC and Mg2+ handling by the DCT. Calcineurin inhibitors paradoxically cause hypomagnesemia in a state of NCC activation, but this may be related to direct effects on TRPM6 gene expression. In Umod-/- mice, the cause of hypomagnesemia may be partly due to both decreased NCC expression and lower TRPM6 expression on the cell surface. This mini-review discusses these new findings and the possible role of altered Na+ flux through NCC and ultimately Na+-K+-ATPase in Mg2+ reabsorption by the DCT.

Sub-chronic microcystin-LR renal toxicity in rats fed a high fat/high cholesterol diet

Microcystin-LR (MCLR) is a liver and kidney toxin produced by cyanobacteria. Recently, it was demonstrated that MCLR exposure drives the progression of high fat/high cholesterol (HFHC) induced nonalcoholic fatty liver disease (NAFLD) to a more severe state. NAFLD is also a risk factor for chronic kidney disease (CKD), and the current study investigated MCLR renal toxicity in the context of an HFHC diet. Sprague Dawley rats were fed either a control diet or an HFHC diet for 10 weeks. After 6 weeks of diet, animals were administered either vehicle, 10 μg/kg, or 30 μg/kg MCLR via intraperitoneal injection every other day for 4 weeks. HFHC diet alone increased the renal glomerular change histopathology score, and 30 μg/kg MCLR exposure increased this score in both the control group and the HFHC group. In contrast, 30 μg/kg MCLR caused greater proteinuria and cast formation and decreased protein phosphatase 1 and 2A protein expression in the HFHC group. Urinary excretion of KIM-1 increased, but albumin and tamm-horsfall protein did not change after MCLR exposure. The general concordance between KIM-1, polyuria, proteinuria, and renal casts after MCLR exposure suggests that proximal tubule cell damage contributed to these connected pathologies. The control group adapted to repeated MCLR exposure by increasing the urinary elimination of MCLR and its metabolites, whereas this adaptation was blunted in the HFHC group. These data suggest an HFHC diet may increase the severity of certain MCLR-elicited renal toxicities.

The Inhibition of NLRP3 Inflammasome and IL-6 Production by Hibiscus noldeae Baker f. Derived Constituents Provides a Link to Its Anti-Inflammatory Therapeutic Potentials.

The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune diseases. Hibiscus noldeae Baker f. has been widely reported to be traditionally used in the treatment of different ailments, some of which are of inflammatory background such as asthma, wounds, headache, etc. However, the claims have not been supported by evidence at the molecular and functional levels. Here, we report on the bio-guided fractionation of H. noldeae and assessment of the inhibitory properties of some fractions and purified compounds on NLRP3 inflammasome and Interleukin 6 (IL-6). The activation of the NLRP3 inflammasome was determined by detecting the activity of caspase-1 and the production of Interleukin 1β (IL-1β) in Lipopolysaccharide (LPS) and ATP-stimulated Tamm-Horsfall Protein 1 (THP-1) macrophages, while the production of IL-6 was studied in LPS-stimulated RAW264.7 mouse macrophages. It was observed that hexane and ethyl acetate fractions of the crude extract of the aerial parts of H. noldeae, as well as caffeic acid, isoquercetin, and ER2.4 and ER2.7 fractions revealed significant inhibitory effects on Caspase-1 activities, and on IL-1β and IL-6 production. The ER2.4 and ER2.7 fractions downregulated the production of IL-1β and IL-6, in a similar range as the caspase-1 inhibitor AC-YVAD-CHO and the drug Dexamethasone, both used as controls, respectively. Overall, our work does provide the very first scientific based evidence for Hibiscus noldeae anti-inflammatory effects and widespread use by traditional healers in Rwanda for a variety of ailments.

Adiponectin's mechanisms in high-density lipoprotein biogenesis and cholesterol efflux

AimAmong adiponectin's beneficial properties is its ability to promote cellular cholesterol efflux, thereby generating high-density lipoprotein (HDL) particles. However, adiponectin's role in the regulation of macrophage lipid metabolism, a crucial process in atherogenesis, remains poorly investigated. The aim of this study was to characterize the adiponectin's role in HDL biogenesis. Methods and resultsWe perform kinetics studies in baby hamster kidney (BHK) and Tamm-Horsfall protein 1 (THP-1) cell lines to elucidate adiponectin's role in HDL biogenesis. In cholesterol-enriched cells, specific molar doses of adiponectin stimulated cholesterol efflux with high efficiency to apoA-I. In the presence of adiponectin, BHK cells expressing ATP binding cassette transporter A1 (ABCA1) or ABCG1 generated lipidated particles having α electrophoretic mobility (α-HDL) and a molecular size of 7.5–20 nm. Interestingly, in THP-1 macrophages, cholesterol efflux was associated with more lipidated preβ1-HDL particles. Direct molecular interaction of adiponectin with apoA-I enhanced the affinity of apoA-I to free cholesterol and resulted in an increase in preβ1-HDL particles from plasma ex vivo. Adiponectin increased ABCA1 and ABCG1 protein expression and activated the formation of ABCA1-linked cholesterol oxidase sensitive plasma membrane domains. ConclusionAdiponectin upregulated ABCA1 and ABCG1 protein expression, reduced lipid accumulation, and efficiently promoted nascent HDL formation. These results highlight that these cellular processes are interconnected through adiponectin and ABCA1- and ABCG1-dependent. In this pathway, adiponectin increased the affinity of apoA-I to cholesterol and effectively accelerated cholesterol removal from the plasma membrane to HDL particles. Thus, by accelerating HDL biogenesis, adiponectin may have therapeutic potential for atherosclerotic cardiovascular disease prevention and management.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25mg would be tested, starting with 10mg in cohort 1. No significant difference between Mirococept at 10mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80mg (equivalent to 120mg in human kidney) that provides a basis for further clinical development.

Is the Well-Recognized Intravascular Tamm-Horsfall Protein Polyp a Misnomer? A Case Report from a Patient with Obstructive Uropathy and Hematuria

Is the Well-Recognized Intravascular Tamm-Horsfall Protein Polyp a Misnomer? A Case Report from a Patient with Obstructive Uropathy and Hematuria

Serum uromodulin is a novel renal function marker in the Japanese population.

Uromodulin, also known as Tamm-Horsfall protein, is the most abundant protein in urine. It has recently been reported that uromodulin exists in a small amount in blood and that its concentration correlates with the estimated glomerular filtration rate (eGFR). First, we generated anti-human uromodulin mouse monoclonal antibodies (mAb(s)) and established a specific enzyme-linked immunosorbent assay (ELISA) for uromodulin. We then performed an observational clinical study to determine if there was a correlation between serum uromodulin concentration and estimates of kidney function and whether the serum uromodulin value could be a biomarker in clinical nephrology. The clinical study included 308 patients with and without chronic kidney disease and healthy volunteers. Serum concentrations of creatinine, cystatin C, and uromodulin were measured and correlations were sought between the eGFR calculated from the creatinine and cystatin C levels and the serum uromodulin concentration. There was a good correlation between the serum uromodulin concentration and the eGFR value calculated from the creatinine (r = 0.76) and cystatin C (r = 0.79) levels. The mean serum uromodulin level in the group with an eGFR > 90mL/min/1.73m2 calculated using cystatin C was significantly higher than that in the group with an eGFR of 80-89mL/min/1.73m2. The serum uromodulin measurement could be a useful biomarker for identification of patients with early deterioration of kidney function.

A Uromodulin Mutation Drives Autoimmunity and Kidney Mononuclear Phagocyte Endoplasmic Reticulum Stress

We identified a family with a UMOD gene mutation (C106F) resulting in glomerular inflammation and complement deposition. To determine if the observed phenotype is due to immune system activation by mutant uromodulin, a mouse strain with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene was generated using CRISPR-Cas9 gene editing and the effect of this mutation on mononuclear phagocytic cells was examined. Mutant mice developed high levels of intracellular and secreted aggregated uromodulin, resulting in anti-uromodulin antibodies and circulating uromodulin containing immune complexes with glomerular deposition and kidney fibrosis with aging. F4/80+ and CD11c+kidney cells phagocytize uromodulin. Differential gene expression analysis by RNA sequencing of F4/80+ phagocytic cells revealed activation of the activating transcription factor 5 (ATF5)-mediated stress response pathway in mutant mice. Phagocytosis of mutant uromodulin by cultured dendritic cells resulted in activation of the endoplasmic reticulum stress response pathway and markers of cell inactivation, an effect not seen with wild-type protein. Mutant mice demonstrate a twofold increase in T-regulatory cells, consistent with induction of immune tolerance, resulting in decreased inflammatory response and improved tissue repair following ischemia-reperfusion injury. The C105F mutation results in autoantibodies against aggregated misfolded protein with immune complex formation and kidney fibrosis. Aggregated uromodulin may induce dendritic cell tolerance following phagocytosis through an unfolded protein/endoplasmic reticulum stress response pathway, resulting in decreased inflammation following tissue injury.

Factors of immune protection in the pathogenesis of urinary infections (literature review)

In recent years, ideas about the pathogenesis of urinary tract infections have been changed significantly. Various pathogenetic factors of microorganisms and new defense mechanisms against them have been discovered. A significant part of pathogens is inactivated by the first line of defense - innate immunity which includes epithelial barriers (mucous membranes), cellular (phagocytes, dendritic cells, NK-cells) and humoral (chemokines, cytokines, complement) components, as well as antimi­crobial proteins). The second and more specific line of defense is the acquired (adaptive) immune system - humoral (B-cells, antibodies) immunity and cellular (T-cells) immunity. However, epithelial cells play an important role in the immune response. These cells interact with the components of both innate immunity and acquired one. Antimicrobial proteins are one of the most ancient and primitive components of the immune system and they are very widely spread in nature. More than 800 antimicro­bial proteins have been described and more than 100 of them have been found in the human body. The mechanism of these proteins is mainly connected with the violation of the bacterial membrane integrity. Nevertheless, some proteins can inhibit protein and/or DNA synthesis. The most common protein in the urine is uromodulin (Tamm-Horsfall protein), synthesized in the thick ascending section of the Henle loop. Uromodulin does not have direct antimicrobial activity, but it is involved in the pathogenesis of many inflammatory kidney diseases. In addition, uromodulin acting through the TLR4 signaling pathway pro­motes the maturation of dendritic cells, thereby further activating innate and acquired immunity. Currently, the role of antimi­crobial proteins and dendritic cells in the pathogenesis of the infectious process is being actively studied. It will probably have a significant practical value. Thus, the development of urinary tract infections is the process of competing for the interaction of the uropathogenic and the macroorganism. The treatment of these diseases (especially chronic) should not be limited to the use of antibacterial drugs. An important component of the pathogen eradication is to increase the activity of its own protective mechanisms.

A novel likely pathogenic variant in the UMOD gene in a family with autosomal dominant tubulointerstitial kidney disease: a case report

BackgroundAutosomal dominant tubulointerstitial kidney disease (ADTKD) caused by a pathogenic variant in UMOD (ADTKD-UMOD) is a rare group of diseases characterized by hyperuricaemia with decreased urinary excretion of urate, gout and progressive chronic kidney disease. The mundane clinical characteristics often result in a failure to diagnose ADTKD-UMOD.Case presentationIn this report, we describe a 12-year-old boy who presented with polyarthritis, hyperuricaemia and tophi with a family history of 8 affected individuals. Clinical data, blood and urine samples of 3 affected members and 8 unaffected members were collected. Genetic testing of the eight genes (UMOD, HPRT1, PRPS1, MTHFR, REN, HNF1b, URAT1 and G6PC) was performed using Sanger sequencing. A heterozygous missense variant (c.674C > G; p.T225R) in UMOD was found in this boy, his older brother with the same phenotype and his mother with hyperuricaemia, gout and chronic kidney disease.ConclusionThis case highlights the importance of family history and genetic testing for definite diagnosis. This novel variant extends the spectrum of known UMOD gene variants and further supports the allelic heterogeneity of ADTKD-UMOD.