Disease and gender-specific dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus.
Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal injury, can bind matrix metalloproteinase-9 (MMP-9) and inhibit its degradation, thereby sustaining MMP-9 proteolytic activity. MMP-9 is produced by renal podocytes, and podocyte MMP production can be modified by high ambient glucose levels. Moreover, dysregulation of MMP-9 activity, gene expression, or urine concentrations has been demonstrated in T2DM-associated nephropathy and in non-diabetic proteinuric renal diseases. Our objective was to determine whether NGAL/MMP-9 dysregulation might contribute to or serve as a biomarker of diabetic nephropathy in type 1 DM (T1DM). Plasma MMP-9, and urine NGAL and MMP-9 concentrations were measured in 121 T1DM and 55 control subjects and examined relative to indicators of glycemia, renal function, and degree of albuminuria. T1DM was associated with a significant increase in urinary excretion of both NGAL and MMP-9, and urine NGAL:Cr (NGAL corrected to urine creatinine) and urine MMP-9:Cr concentrations were highly correlated with each other. Both were also positively correlated with measurements of glycemic control and with albuminuria. Plasma MMP-9, urine MMP-9, and urine NGAL concentrations were significantly higher in females compared to males, and urine MMP-9:Cr concentrations displayed a menstrual cycle specific pattern. Increased urinary excretion of NGAL and MMP-9 supports a role for NGAL/MMP-9 dysregulation in renal dysfunction; moreover, gender-specific differences could support a gender contribution to pathological mechanisms or susceptibility for the development of renal complications in diabetes mellitus.
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA. thrailkillkathrynm@uams.edu
Kathryn M
KM
Thrailkill
Cynthia S
CS
Moreau
Gael E
GE
Cockrell
Chan-Hee
CH
Jo
Robert C
RC
Bunn
Alba E
AE
Morales-Pozzo
Charles K
CK
Lumpkin
John L
JL
Fowlkes
D000209:Acute-Phase Proteins / Q000235:genetics / Q000652:urine*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000419:Albuminuria / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007677:Kidney Function Tests; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000652:urine*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics / Q000652:urine*; D050199:Podocytes / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000652:urine*; D012727:Sex Characteristics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D055815:Young Adult
D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9