Cellular basis of diabetic nephropathy: II. The transforming growth factor-beta system and diabetic nephropathy lesions in type 1 diabetes.
Transforming growth factor-beta (TGF-beta) may be critical in the development of diabetic nephropathy (DN), and genetic predisposition is an important determinant of DN risk. We evaluated mRNA expression levels of TGF-beta system components in cultured skin fibroblasts (SFs) from type 1 diabetic patients with fast versus slow development of DN. A total of 125 long-standing type 1 diabetic patients were ranked by renal mesangial expansion score (MES) based on renal biopsy findings and diabetes duration. Patients in the highest quintile of MES who were also microalbuminuric or proteinuric (n = 16) were classified as "fast-track" for DN, while those in the lowest quintile who were also normoalbuminuric (n = 23) were classsified as "slow-track" for DN. Twenty-five normal subjects served as control subjects. SFs were cultured in medium with 25 mmol/l glucose for 36 h. SF mRNA expression levels for TGF-beta1, TGF-beta type II receptor (TGF-beta RII), thrombospondin-1, and latent TGF-beta binding protein-1 (LTBP-1) were measured by real-time RT-PCR. LTBP-1 mRNA expression was reduced in slow-track (0.99 +/- 0.38) versus fast-track patients (1.65 +/- 0.52, P = 0.001) and control subjects (1.41 +/- 0.7, P = 0.025). mRNA levels for TGF-beta1, TGF-beta RII, and thrombospondin-1 were similar in the three groups. Reduced LTBP-1 mRNA expression in SFs from slow-track patients may reflect genetically determined DN protection and suggests that LTBP-1 may be involved in the pathogenesis of DN through the regulation of TGF-beta activity.
Huang
Chunmei
C
Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Kim
Youngki
Y
Caramori
Maria Luiza A
ML
Fish
Alfred J
AJ
Rich
Stephen S
SS
Miller
Michael E
ME
Russell
Gregory B
GB
Mauer
Michael
M
D000328:Adult; D000419:Albuminuria / Q000209:etiology; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology*; D053779:Latent TGF-beta Binding Proteins; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012016:Reference Values; D012867:Skin / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000235:genetics; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II