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.
Thrailkill
Kathryn M
KM
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA. thrailkillkathrynm@uams.edu
Moreau
Cynthia S
CS
Cockrell
Gael E
GE
Jo
Chan-Hee
CH
Bunn
Robert C
RC
Morales-Pozzo
Alba E
AE
Lumpkin
Charles K
CK
Fowlkes
John L
JL
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