Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy.

BACKGROUND In patients with type 1 diabetes, some consider microalbuminuria to be a predictor of diabetic nephropathy while others believe it is an early feature of diabetic nephropathy. METHODS Levels of mRNAs that are of pathogenetic relevance in diabetic nephropathy were compared in glomeruli isolated from microalbuminuric and overtly proteinuric subjects and in control normoalbuminuric diabetic subjects and living renal transplant donors. RESULTS In subjects with microalbuminuria and overt proteinuria, glomerular mRNAs were virtually identical and approximately twofold higher for connective tissue growth factor (CTGF; P < 0.01) and collagen alpha2(IV) (P < 0.03) compared to living renal donors and normoalbuminuric patients. Glomerular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels were not significantly different among the groups (P = 0.4). Weak but statistically significant correlations were noted between CTGF mRNA and albuminuria (assessed by rank), fractional mesangial surface area, and a composite renal biopsy index. Glomerular CTGF mRNA correlated inversely with creatinine clearance. Glomerular collagen alpha2(IV) mRNA levels correlated with albuminuria (by rank) and less strongly with fractional mesangial area. CONCLUSION To our knowledge, these data provide the first biochemical evidence demonstrating that the glomeruli of microalbuminuric patients and those with overt proteinuria do not differ significantly. The data support the concept that microalbuminuria is not "predictive" of diabetic nephropathy, but rather is an earlier point in the spectrum of diabetic nephropathy.

[1]  G. Striker,et al.  Glomerular type IV collagen in patients with diabetic nephropathy with and without additional glomerular disease. , 2000, Kidney international.

[2]  L. Thal,et al.  Blood Levels of Alpha-1-Antichymotrypsin and Risk Factors for Alzheimer’s Disease: Effects of Gender and Apolipoprotein E Genotype , 2000, Dementia and Geriatric Cognitive Disorders.

[3]  Gary R. Grotendorst,et al.  Connective tissue growth factor mediates transforming growth factor β‐induced collagen synthesis: down‐regulation by cAMP , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  A. Risch,et al.  Mapping AAC1, AAC2 and AACP, the genes for arylamine N-acetyltransferases, carcinogen metabolising enzymes on human chromosome 8p22, a region frequently deleted in tumours. , 1997, Cytogenetics and cell genetics.

[5]  P. Lai,et al.  Glomerular transforming growth factor-beta1 mRNA as a marker of glomerulosclerosis-application in renal biopsies. , 1997, Nephron.

[6]  H. Abboud,et al.  Expression of Transforming Growth Factor-β and Type IV Collagen in Early Streptozotocin-Induced Diabetes , 1997, Diabetes.

[7]  C. Esposito,et al.  Molecular analysis of glomerular diseases in renal biopsies , 1996, Proceedings of the Association of American Physicians.

[8]  G. Viberti Prognostic significance of albuminuria for the development of nephropathy , 1995, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[9]  M. Steffes,et al.  Glomerular Structure in Nonproteinuric IDDM Patients With Various Levels of Albuminuria , 1994, Diabetes.

[10]  M. Razzaque,et al.  In situ localization of type III and type IV collagen‐expressing cells in human diabetic nephropathy , 1994, The Journal of pathology.

[11]  R. Butkowski,et al.  Glomerular distribution of type IV collagen in diabetes by high resolution quantitative immunochemistry. , 1994, Kidney international.

[12]  Y. Tomino,et al.  ECM Gene Expression and Its Modulation by Insulin in Diabetic Rats , 1992, Diabetes.

[13]  D. Woodrow,et al.  Diabetic glomerulosclerosis—immunogold ultrastructural studies on the glomerular distribution of type IV collagen and heparan sulphate proteoglycan , 1992, The Journal of pathology.

[14]  E. Schleicher,et al.  Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. , 1991, The American journal of pathology.

[15]  H. Makino,et al.  Changes in glomerular extracellular matrices components in diabetic nephropathy. , 1991, The Journal of diabetic complications.

[16]  D. Noonan,et al.  Altered Steady-State mRNA Levels of Basement Membrane Proteins in Diabetic Mouse Kidneys and Thromboxane Synthase Inhibition , 1990, Diabetes.

[17]  R. Bilous,et al.  Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria. , 1989, The New England journal of medicine.

[18]  C. Mogensen,et al.  Predicting diabetic nephropathy in insulin-dependent patients. , 1984, The New England journal of medicine.

[19]  A. Michael,et al.  Polyantigenic Expansion of Basement Membrane Constituents in Diabetic Nephropathy , 1983, Diabetes.

[20]  H. Parving,et al.  Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion. , 1982, Acta endocrinologica.

[21]  J. Yee,et al.  Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. , 2000, Journal of the American Society of Nephrology : JASN.

[22]  G. Viberti,et al.  Predicting diabetic nephropathy. , 1984, The New England journal of medicine.