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

Abstract

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. 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. Because the impact of diabetes on RNase 7 expression and function are unknown, we investigated the effects of insulin on RNase 7 using human urine specimens. The urinary RNase 7 concentrations were measured in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared with controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, the mechanisms by which insulin stimulates RNase 7 synthesis were next explored. Insulin induced RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, uropathogenic E. coli suppressed PI3K/AKT activity and RNase 7 production. Thus, insulin and PI3K/AKT signaling are essential for RNase 7 expression and increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. Our data may provide unique insight into novel urinary tract infection therapeutic strategies in at-risk populations.

• Authors: Tad E Eichler, Brian Becknell, Robert S Easterling, Susan E Ingraham, Daniel M Cohen, Andrew L Schwaderer, David S Hains, Birong Li, Ariel Cohen, Jackie Metheny, Susheela Tridandapani, John David Spencer
• Journal: Kidney international (Kidney Int) Vol. 90 Issue 3 Pg. 568-79 (09 2016) ISSN: 1523-1755 [Electronic] United States
• PMID: 27401534 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• Insulin
• INSR protein, human
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt
• Ribonucleases
• Ribonuclease 7

Topics

• Adolescent
• Antigens, CD (metabolism)
• Cell Line, Tumor
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1 (complications, drug therapy, metabolism, urine)
• Escherichia coli (isolation & purification)
• Escherichia coli Infections (etiology, metabolism, microbiology, urine)
• Female
• Humans
• Insulin (metabolism, therapeutic use)
• Male
• Middle Aged
• Phosphatidylinositol 3-Kinases (metabolism)
• Primary Cell Culture
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, Insulin (metabolism)
• Ribonucleases (metabolism, urine)
• Signal Transduction
• Urinary Tract (metabolism, microbiology)
• Urinary Tract Infections (etiology, metabolism, microbiology, urine)