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DEFA1A3 DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection.

ABSTRACT: Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3 participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations in DEFA1A3 have been associated with severity and outcomes in infectious diseases including urinary tract infections (UTIs). Specifically, children with lower DNA copy numbers were more susceptible to UTIs. The mechanism of action by which α-Defensin 1-3/DEFA1A3 copy-number variations lead to UTI susceptibility remains to be explored. In this study, we use a previously characterized transgenic knock-in of the human DEFA1A3 gene mouse to dissect α-Defensin 1-3 gene dose-dependent antimicrobial and immunomodulatory roles during uropathogenic Escherichia coli (UPEC) UTI. We elucidate the relationship between kidney neutrophil- and collecting duct intercalated cell-derived α-Defensin 1-3/DEFA1A3 expression and UTI. We further describe cooperative effects between α-Defensin 1-3 and other AMPs that potentiate the neutralizing activity against UPEC. Cumulatively, we demonstrate that DEFA1A3 directly protects against UPEC meanwhile impacting pro-inflammatory innate immune responses in a gene dosage-dependent manner.

SUBMITTER: Canas JJ

PROVIDER: S-EPMC10997819 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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DEFA1A3 DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection.

Canas Jorge J JJ Arregui Samuel W SW Zhang Shaobo S Knox Taylor T Calvert Christi C Saxena Vijay V Schwaderer Andrew L AL Hains David S DS

Life science alliance 20240405 6

Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3 participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations in DEFA1A3 have been associated with severity and outcomes in infectious diseases including urinary tract infections (UTIs). Specifically, children with lower DNA copy numbers were more susceptib ...[more]

PMID: 38580392

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Project description:BackgroundTo evaluate the feasibility and effect of upper urinary tract videourodynamics in complex reconstructed upper urinary tract.MethodsFrom January 2016 to December 2018, patients who underwent complex upper urinary tract reconstruction and received upper urinary tract videourodynamics were included in the study. The modified Whitaker test was performed at 3 months after operation. The relative pelvic pressure was defined as the pelvic pressure minus the bladder pressure. Based on the flow rate, the test was divided into physiological phase and high flow phase. The results of pressure and image were classified into 3 types. Successful nephrostomy removal was defined as no symptoms and improved or stable hydronephrosis.ResultsA total of 12 patients who underwent complex upper urinary tract reconstruction received modified Whitaker test. All tests were successfully completed without adverse reactions. The relative pelvic pressure of 3 patients kept steady near the baseline throughout the examination and was classified into type 1. The pelvic pressure of 7 patients increased as the perfusion continued, and the relative pressure dropped to relative low level due to the peristalsis of ureter (type 2). The pressure of 2 patients increased along with increasing perfusion speed, and the relative pelvis pressure could easily reach 15 cmH2O. The peristalsis of ureter disappeared or appeared very weakly on the video record (type 3). Patients in type 1 (3 cases) and type 2 (7 cases) groups were allowed to remove the nephrostomy tube immediately. Patients in type 3 group needed to keep the nephrostomy for close follow up, and the tubes were removed 2 weeks and 4 weeks after the examination, respectively. None of the 12 patients received further treatment for recurrent symptoms and exacerbation of hydronephrosis.ConclusionsThe modified Whitaker test is initially safe and feasible in postoperative evaluation of complex upper urinary tract reconstruction surgery. Detailed results can provide more evidence to judge whether nephrostomy tube could be removed safely.

Project description:Simple Summary It’s difficult to detect upper tract urothelial carcinoma at early stage. Invasive testing may increase risk of cancer recurrences in the bladder after radical nephroureterectomy. Thus, in the present study, we incorporated two-gene mutation and methylation biomarkers to conduct the diagnostic tool of upper tract urothelial carcinoma and performed external validation to investigate the utility and stability of the optimal panel. It showed a highly specific and robust performance. It may be used as a replaceable approach for early detection of upper tract urothelial carcinoma, resulting in less extensive examinations in patients at low risk. Abstract Background: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). Methods: In this cohort study we recruited 402 patients from six Hunan hospitals who underwent ureteroscopy for hematuria, including 95 patients with UTUC and 307 patients with non-UTUC findings. Midstream morning urine samples were collected before ureteroscopy and surgery. DNA was extracted and qPCR was used to analyze mutations in TERT and FGFR3 and the methylation of NRN1. In the training set, the random forest algorithm was used to build an optimal panel. Lastly, the Beijing cohort (n = 76) was used to validate the panel. Results: The panel combining the methylation with mutation markers led to an AUC of 0.958 (95% CI: 0.933–0.975) with a sensitivity of 91.58% and a specificity of 94.79%. The panel presented a favorable diagnostic value for UTUC vs. other malignant tumors (AUC = 0.920) and UTUC vs. benign disease (AUC = 0.975). Furthermore, combining the panel with age revealed satisfactory results, with 93.68% sensitivity, 94.44% specificity, AUC = 0.970 and NPV = 98.6%. In the external validation process, the model showed an AUC of 0.971, a sensitivity of 95.83% and a specificity of 92.31, respectively. Conclusions: A novel diagnostic model for analyzing hematuria patients for the risk of UTUC was developed, which could lead to a reduction in the need for invasive examinations. Combining NRN1 methylation and gene mutation (FGFR3 and TERT) with age resulted in a validated accurate prediction model.

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DEFA1A3 DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection.

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<i>DEFA1A3</i> DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection.

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