Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses

Murtha, Matthew; Eichler, Tad; Bender, Kristin; Metheny, Jackie D.; Li, Birong; Schwaderer, Andrew L.; Mosquera, Claudia; James, Cindy L.; Schwartz, Laura; Becknell, Brian; Spencer, John David

doi:10.1172/jci98595

Cited by 36 publications

(49 citation statements)

References 58 publications

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“…We used the direct bladder inoculation model because previously published work from our research group and others demonstrates that it is difficult to establish pyelonephritis by transurethrally infecting nonrefluxing mice. 19,36,38,39 Here, the direct bladder inoculation model is advantageous in that it allowed us to inoculate male mice, maximized the usage of generated mice (i.e., using male mice for UTI which may otherwise be euthanized), and provided an avenue to investigate the role of RNase 7 during upper urinary tract infection. Although our current experimental design does not evaluate sex-specific UTI response, our results using both models show that RNase 7 contributes to upper and lower urinary tract defense against UPEC.…”

Section: Rnase 7 As a Uti Prognosticmentioning

confidence: 99%

“…For example, we have shown that insulin enhances RNase 4 and RNase 7 expression via PI3K/AKT signaling. 19,33 Thus, future studies may have clinical impact investigating how the insulin-PI3K/ AKT-RNase 7 axis can be used to prevent or treat infections. Similarly, another potential strategy is to combine antibiotic therapy with novel immune modulators that enhance RNase 7 expression.…”

Section: Rnase 7 As a Uti Prognosticmentioning

confidence: 99%

“…15,18 Our published data suggest that RNase 7 may be an ideal AMP to develop as a UTI therapeutic target because it has potent bactericidal activity against UPEC and multidrug-resistant (MDR) UPEC strains, minimal toxicity, is produced by the bladder urothelium and kidney's intercalated cells (cell types targeted by UPEC), and is abundant in human urine. 14,15,19 On a per-molar basis, RNase 7 has been identified as one of the most potent human AMPs. 20 Currently, there is limited evidence evaluating RNase 7's antimicrobial activity in model systems.…”

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confidence: 99%

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Ribonuclease 7 Shields the Kidney and Bladder from Invasive Uropathogenic Escherichia coli Infection

Eichler¹,

Bender²,

Murtha

et al. 2019

JASN

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BackgroundEvidence suggests that antimicrobial peptides, components of the innate immune response, protect the kidneys and bladder from bacterial challenge. We previously identified ribonuclease 7 (RNase 7) as a human antimicrobial peptide that has bactericidal activity against uropathogenic Escherichia coli (UPEC). Functional studies assessing RNase 7’s contributions to urinary tract defense are limited.MethodsTo investigate RNase 7’s role in preventing urinary tract infection (UTI), we quantified urinary RNase 7 concentrations in 29 girls and adolescents with a UTI history and 29 healthy female human controls. To assess RNase 7’s antimicrobial activity in vitro in human urothelial cells, we used siRNA to silence urothelial RNase 7 production and retroviral constructs to stably overexpress RNase 7; we then evaluated UPEC’s ability to bind and invade these cells. For RNase 7 in vivo studies, we developed humanized RNase 7 transgenic mice, subjected them to experimental UTI, and enumerated UPEC burden in the urine, bladder, and kidneys.ResultsCompared with controls, study participants with a UTI history had 1.5-fold lower urinary RNase 7 concentrations. When RNase 7 was silenced in vitro, the percentage of UPEC binding or invading human urothelial cells increased; when cells overexpressed RNase 7, UPEC attachment and invasion decreased. In the transgenic mice, we detected RNase 7 expression in the kidney’s intercalated cells and bladder urothelium. RNase 7 humanized mice exhibited marked protection from UPEC.ConclusionsThese findings provide evidence that RNase 7 has a role in kidney and bladder host defense against UPEC and establish a foundation for investigating RNase 7 as a UTI prognostic marker or nonantibiotic-based therapy.

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Section: Rnase 7 As a Uti Prognosticmentioning

confidence: 99%

Section: Rnase 7 As a Uti Prognosticmentioning

confidence: 99%

mentioning

confidence: 99%

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Ribonuclease 7 Shields the Kidney and Bladder from Invasive Uropathogenic Escherichia coli Infection

Eichler¹,

Bender²,

Murtha

et al. 2019

JASN

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“…Traditionally, glycosuria has been presented as the likely culprit, the glucose providing a more favorable environment for bacterial growth. However, the report in this issue of the JCI by Murtha et al suggests that urinary sugar is likely not the full story behind UTI in the diabetic (13).…”

Section: Uti In Diabeticsmentioning

confidence: 94%

Why are diabetics prone to kidney infections?

Zasloff¹

2018

Journal of Clinical Investigation

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“…8 In their recent paper, Spencer et al evaluated a critical clinical question: why do diabetics have more frequent UTIs? 9 Any of the mechanisms described above could be the target of diabetes, and the presence of glucose in the urine could also stimulate the growth of bacteria, as has become evident with the use of SGLT2 inhibitors.…”

Section: Disclosurementioning

confidence: 99%