Insulin Downregulated the Infection of Uropathogenic Escherichia coli (UPEC) in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway

Abstract

Diabetic individuals have a higher incidence of urinary tract infection (UTI) than non-diabetic individuals, and also require longer treatment. We evaluated the effects of insulin pretreatment on the regulation of JAK/STAT transduction pathways in UPEC-infected bladder cells in a high-glucose environment. A bladder cell model with GFP-UPEC and fluorescent-labeled TLR4, STAT1, STAT3, and insulin receptor antibodies, was used to evaluate the relationship between insulin receptor signaling, TLR-4-mediated, and JAK/STAT-dependent pathways. Pretreatment with 20 and 40 µg/mL insulin for 24 h significantly and dose-dependently reduced UPEC infection in SV-HUC-1 cells. Additionally, the expression levels of STAT1 and STAT3 were downregulated in a dose-dependent manner. However, insulin receptor (IR) expression was not affected by insulin pretreatment. Our results showed that insulin-mediated reduction of UPEC infection in a high-glucose environment was not only due to the downregulation of JAK1/2 and phosphorylated STAT-1/3, but also because of the decreased expression of TLR-4 proteins and pro-inflammatory IL-6. Here, we demonstrated that insulin reduced not only UPEC infection in bladder epithelial cells, but also inhibited the JAK/STAT transduction pathway during infection in a high-glucose environment. This study provides evidence to support the use of insulin in the treatment of UPEC infection in patients with type 2 diabetes (T2D).

Serratia fonticola and its role as a single pathogen causing emphysematous pyelonephritis in a non-diabetic patient: A case report

“…In previous studies, diabetes was present in 96%-98% of all patients with EPN[ 2 , 3 ], and renal calculi was an antecedent in approximately 7.84%[ 2 ]. In general, gas-forming bacteria are the cause of emphysematous infections, but when it comes to pyelonephritis, the infection is attributed to Escherichia coli in more than 50% of cases and less often to other gram-negative bacteria[ 7 ].…”

“…It has been stated that even when agent-related virulence factors, along with the underlying health condition of patients, may predispose them to EPN, diabetes mellitus with poor glycemic control has been independently associated with the odds of developing EPN[ 3 ]. Furthermore, evidence in Escherichia coli urinary tract infections suggests that insulin treatment in infected patients with diabetes may downregulate infection, which is congruent with the role of glycemic control in EPN in urinary tract infections[ 4 ].…”

Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway

“…Our laboratory has verified that sugar enhances UPEC-induced bladder cell infection and inflammation by activating TLR-4- and JAK/STAT1-dependent pathways [ 26 ]. We recently demonstrated that insulin could reduce JAK/STAT-pathway-regulated UPEC infections in bladder cells in a high-glucose environment [ 20 ]. However, in comparison with insulin, which mainly acts on blood sugar stabilization and diabetes treatment, more effective biological drugs are warranted to improve UPEC infection in the urinary tract in a high-glucose environment.…”

“…However, the immunomechanism of cellular regulation is not mediated via a single pathway. We recently demonstrated that insulin downregulates the infection of UPEC in bladder cells in a high-glucose environment via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway [ 20 ]. Whether JAK/STAT signaling transduction pathways are involved in the regulation of AMPs, especially LCN2 production, to achieve a vital effect in UTI defense was our focus.…”

Cycle Biodynamics of Women’s Microbiome in the Urinary and Reproductive Systems

“…The exploration and investigation of alternative immunomodulatory therapies, such as cranberry extract (which increases the Tamm–Horsfall glycoprotein to inhibit bacterial adhesion) [ 60 , 61 , 62 , 63 ], vitamin C and anthocyanins (which inhibit reactive oxygen species production to prevent urinary infections) [ 64 , 65 , 66 , 67 ], dietary restriction of iron, and lactoferrin supplementation (which reduces bacterial density in the urinary tract, particularly in cases with siderophore characteristics) [ 68 , 69 ], and subcutaneous insulin injections in diabetic patients (to promote the secretion of RNase 7, RNase4, and lipocalin-2 to prevent cystitis) [ 70 , 71 ], as well as vaccines [ 72 , 73 ] and probiotics [ 52 ], present promising avenues for future medical advancements. However, studies that investigated the use of immunomodulatory therapies as alternatives to antibiotics currently lack clinical significance, leading to a debate on the use and applications of these therapies.…”