Antimicrobial peptides are essential host defense mechanisms that prevent urinary tract infections. Recent studies demonstrate that peptides in the Ribonuclease A Superfamily have antimicrobial activity against uropathogens and protect the urinary tract from uropathogenic Escherichia coli (UPEC). Little is known is about the antibacterial function or expression of Ribonuclease 4 in the human urinary tract. Here, we show that full-length recombinant Ribonuclease 4 peptide and synthetic amino-terminal Ribonuclease 4 peptide fragment have antibacterial activity against UPEC and multi-drug resistant UPEC. RNASE4 transcript expression was detected in human kidney and bladder tissue using quantitative real-time polymerase chain reaction. Immunostaining or in situ hybridization localized Ribonuclease 4 expression to proximal tubules, principal and intercalated cells in the kidney's collecting duct, and the bladder urothelium. Urinary Ribonuclease 4 concentrations were quantified in healthy controls and females with a urinary tract infection history. Compared to controls, urinary RNase 4 concentrations were significantly lower in females with a urinary tract infection history. When Ribonuclease 4 was neutralized in human urine or silenced in vitro using small interfering RNA, urinary UPEC replication or attachment to and invasion of urothelial and kidney medullary cells increased. These data show that Ribonuclease 4 has antibacterial activity against UPEC, is expressed in the human urinary tract, and can contribute to host defense against urinary tract infections.
BackgroundDiabetic nephropathy (DN) is one of the most common microvascular complications in type 1 diabetes Mellitus (T1D). Urinary markers of renal damage or oxidative stress may signal early stages of DN. The association of these markers with blood pressure (BP) patterns and glycemic variability (GV) in children is yet to be explored.MethodsSubjects between the ages of 10 and 21 years with T1D were enrolled. Continuous glucose monitoring (CGM) and ambulatory blood pressure monitoring (ABPM) were performed on each subject. Urine samples were collected and analyzed for albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) and pentosidine.ResultsThe study included 21 subjects (62% female) with median age of 16.8 (IQR: 14.5, 18.9). Median HbA1C was 8.4 (IQR: 7.5, 9.3). While microalbuminuria was negative in all but one case (4.8%), urinary NGAL/Cr and pentosidine/Cr ratios were significantly elevated (P<0.001) in diabetic patients despite having normal microalbuminuria, and they correlated significantly with level of microalbumin/Cr (r=0.56 [CI: 0.17, 0.8] and r=0.79 [CI: 0.54, 0.91], respectively). Using ABPM, none had hypertension, however, poor nocturnal systolic BP dipping was found in 48% of cases (95% CI: 28-68%). Urinary NGAL/Cr negatively correlated with nocturnal SBP dipping (r=-0.47, CI: -0.76, -0.03). Urine NGAL/Cr also showed a significant negative correlation with HbA1c measurements, mean blood glucose, and high blood glucose index (r=-0.51 [CI: -0.78, -0.09], r=-0.45 [CI: -0.74, -0.03], and r=-0.51 [CI: -0.77, -0.1], respectively). Median urinary NGAL/Cr and pentosidine/Cr ratios were higher in the high GV group but were not significantly different.DiscussionThis pilot study explores the role of ABPM and urinary markers of tubular health and oxidative stress in early detection of diabetic nephropathy. GV may play a role in the process of this diabetic complication.
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