An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract

Spencer, John David; Schwaderer, Andrew L.; Eichler, Tad; Wang, Huanyu; Kline, Jennifer; Justice, Sheryl S.; Cohen, Daniel M.

doi:10.1038/ki.2013.395

Cited by 31 publications

(45 citation statements)

References 49 publications

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“…99 Incubation of human urine with neutralizing antibodies to RNase 7 results in a significant increase in bacterial growth in response to inoculation with UPEC. 98,104 The addition of recombinant RNase 7 peptide to cultured UPEC results in bactericidal and bacteriostatic activity at low micromolar concentrations, matching levels observed in human urine. 99,103 These findings suggest that RNase 7 constitutes a front-line epithelial-derived shield against invading uropathogens.…”

Section: β-Defensinsmentioning

confidence: 69%

“…Expression of ribonuclease inhibitor decreases in pyelonephritis, attributed at least in part to its proteolytic degradation. 104,105 In addition, oxidation of the 32 cysteine residues of ribonuclease inhibitor in response to pyelonephritis might abrogate the interaction of ribonuclease inhibitor with RNase 7. 106 Either of these scenarios could liberate RNase 7 to destroy invading bacteria.…”

Section: β-Defensinsmentioning

confidence: 99%

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Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

et al. 2015

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Urinary tract infections (UTIs), including pyelonephritis, are among the most common and serious infections encountered in nephrology practice. UTI risk is increased in selected patient populations with renal and urinary tract disorders. As the prevalence of antibiotic-resistant uropathogens increases, novel and alternative treatment options will be needed to reduce UTI-associated morbidity. Discoveries over the past decade demonstrate a fundamental role for the innate immune system in protecting the urothelium from bacterial challenge. Antimicrobial peptides, an integral component of this urothelial innate immune system, demonstrate potent bactericidal activity toward uropathogens and might represent a novel class of UTI therapeutics. The urothelium of the bladder and the renal epithelium secrete antimicrobial peptides into the urinary stream. In the kidney, intercalated cells--a cell-type involved in acid-base homeostasis--have been shown to be an important source of antimicrobial peptides. Intercalated cells have therefore become the focus of new investigations to explore their function during pyelonephritis and their role in maintaining urinary tract sterility. This Review provides an overview of UTI pathogenesis in the upper and lower urinary tract. We describe the role of intercalated cells and the innate immune response in preventing UTI, specifically highlighting the role of antimicrobial peptides in maintaining urinary tract sterility.

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Section: β-Defensinsmentioning

confidence: 69%

Section: β-Defensinsmentioning

confidence: 99%

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

et al. 2015

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“…The AMPs typically disrupt the phospholipid membranes of different types of microorganisms, including both bacteria and fungi, rather than target a specific species (56,57). RNase7, for example, inhibits Gram -E. coli, Pseudomonas, and Proteus as well as Gram + Enterococcus and Staphyloccocus (58). Lactoferrin and THP also inhibit both Gram + and Gram -organisms (59).…”

Section: Introductionmentioning

confidence: 99%

α–Intercalated cells defend the urinary system from bacterial infection

Paragas¹,

Kulkarni²,

Werth³

et al. 2014

J. Clin. Invest.

129

111

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α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2. The presence of LCN2 in urine was both necessary and sufficient to control the urinary tract infection through iron sequestration, even in the harsh condition of urine acidification. In mice lacking A-ICs, both urinary LCN2 and urinary acidification were reduced, and consequently bacterial clearance was limited. Together these results indicate that A-ICs, which are known to regulate acid-base metabolism, are also critical for urinary defense against pathogenic bacteria. They respond to both cystitis and pyelonephritis by delivering bacteriostatic chemical agents to the lower urinary system.

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“…13, 19, 20 When it is neutralized in human urine specimens, urinary bacterial growth increases – suggesting that deficient urinary RNase 7 production increases UTI susceptibility. 12, 21 …”

Section: Introductionmentioning

confidence: 99%

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

Eichler

Becknell

Easterling

et al. 2016

Kidney International

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Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site of infection. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. The impact of diabetes on RNase 7 expression and function are unknown. Here, we investigate the effects of insulin on RNase 7. Using human urine specimens, we measured urinary RNase 7 concentrations in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared to controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, we explored the mechanisms by which insulin induces RNase 7. Insulin induces RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, we show that uropathogenic E. coli suppresses PI3K/AKT and RNase 7. Together, these results indicate that insulin and PI3K/AKT signaling are essential for RNase 7 expression. They also suggest that increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. These data may provide unique insight into novel UTI therapeutic strategies in at risk populations.

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An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract

Cited by 31 publications

References 49 publications

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

α–Intercalated cells defend the urinary system from bacterial infection

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

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