Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder

Abstract

Diabetes is known to increase susceptibility to infections, partly due to impaired granulocyte function and changes in the innate immunity. Here, we investigate the effect of diabetes, and high glucose on the expression of the antimicrobial peptide, psoriasin and the putative consequences for E. coli urinary tract infection. Blood, urine, and urine exfoliated cells from patients are studied. The influence of glucose and insulin is examined during hyperglycemic clamps in individuals with prediabetes and in euglycemic hyperinsulinemic clamped patients with type 1 diabetes. Important findings are confirmed in vivo in type 2 diabetic mice and verified in human uroepithelial cell lines. High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function together with altering cell membrane proteins and cytoskeletal elements, resulting in increasing bacterial burden. Estradiol treatment restores the cellular function with increasing psoriasin and bacterial killing in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia. In conclusion, our findings present the effects and underlying mechanisms of high glucose compromising innate immunity.

MV140 mucosal bacterial vaccine improves uropathogenic E. coli clearance in an experimental model of urinary tract infection

“…Given the rapid bacterial clearance kinetics in MV140-immunized mice compared to controls, we next assessed the differential production of antimicrobial peptides by the urothelium. Cramp (cathelicidin-related antimicrobial peptide) and psoriasin (S100a7a) levels which have been shown to be activated during a UTI (10,11) were analyzed. A slight close-to-significant increase in bladder expression of psoriasin (p = 0.051) was detected by qPCR at 24h p.i.…”

Altered Expression of Antimicrobial Peptides in the Upper Gastrointestinal Tract of Patients with Diabetes Mellitus

“…Our findings may be supported by recent publications that showed decreased HBD-1, HBD-2 and HBD-3 levels in the saliva of patients with T2DM and decreased HBD-3 levels in saliva of patients with type 1 diabetes [ 39 , 40 ]. Mohanty et al [ 41 ] detected decreased levels of the antimicrobial protein psoriasin in the plasma and urine exfoliated cells of patients with high blood glucose levels. Psoriasin was also decreased in human urothelial cell lines cultured under high glucose conditions and in the urinary bladder of type 2 diabetic mice, backing the hypothesis that a hyperglycemic metabolic state may compromise innate immunity.…”

Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens

“…For instance, high extracellular glucose treatment lowers the abundance of psoriasin (S100A7), RNAse7, and Defensin b4 in uroepithelial cells and urine exfoliated cells from patients with diabetes. [52][53][54] In addition, peak performance of AMPs has been shown at urinary pH 5-6.5, 55 although pH has variable effects. While alkaline extracellular pH reduces RNAse7 activity, b defensin 1 remains unaffected.…”