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 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.

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

“…Additionally, while this study shows the key role for collecting duct IR-mediated signaling in UTI prevention, it does not provide mechanistic insight into the effects of insulin signaling in the lower urinary tract. As shown here and in our prior publication, IR is expressed in murine and human bladder (17). Finally, in regard to our human studies, youth in the T2DM cohort were receiving DM therapies.…”

“…Cohort studies show that people with T1DM have lower serum AMP concentrations of cathelicidin and BD-1 (49). Similarly, children with insulin-deficient T1DM have suppressed urinary RNase7 concentrations that increase with insulin therapy (17). Here, we collected random urine specimens from control and T2DM children and adolescents, and showed that T2DM youth have suppressed urinary RNase4 and Lcn2 concentrations.…”

“…Although the causes of insulin resistance are unclear, key mechanisms include disrupted IR signaling or decreased IR expression (8,9). Published evidence shows that kidneys from insulin-resistant rats have suppressed medullary and collect- Recently, we published in vitro data showing insulin induces RNase7 expression in human renal epithelial cells via PI3K/AKT signaling (17). Prior studies show that insulin upregulates Lcn2 production in omental adipose tissue explants.…”

“…Recently, we demonstrated that insulin and insulin-mediated PI3K/AKT activation contribute to renal host defenses by inducing antimicrobial peptide (AMP) production (17). In the kidney, AMPs are primarily produced by intercalated cells (ICs).…”

The burden of common infections in children and adolescents with diabetes mellitus: A Pediatric Health Information System study

“…These functions are restored with insulin therapy. [56][57][58][59][60] In addition, the hyperglycemic environment can suppress neutrophil mobilization and degranulation, inhibit monocytic phagocytosis, alter leukocyte profiles, and suppress cytokine and chemokine gene expression. 19 formation, or acute kidney injury).…”