Cellular Basis of Diabetic Nephropathy
II. The Transforming Growth Factor-β System and Diabetic Nephropathy Lesions in Type 1 Diabetes
- Chunmei Huang1,
- Youngki Kim1,
- Maria Luiza A. Caramori1,
- Alfred J. Fish2,
- Stephen S. Rich2,
- Michael E. Miller2,
- Gregory B. Russell2 and
- Michael Mauer1
- 1Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
- 2Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Transforming growth factor-β (TGF-β) 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-β 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-β1, TGF-β type II receptor (TGF-β RII), thrombospondin-1, and latent TGF-β 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-β1, TGF-β 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-β activity.
Address correspondence and reprint requests to Michael Mauer, MD, Pediatric Nephrology, MMC 491 UMHC, Delaware St. S.E., Minneapolis, MN 55455. E-mail:.
Received for publication 4 April 2002 and accepted in revised form 4 September 2002.
AER, albumin excretion rate; Ct, threshold cycle; DMEM, Dulbecco’s modified Eagle’s medium; DN, diabetic nephropathy; ECM, extracellular matrix; GFR, glomerular filtration rate; LAP, latency-associated peptide; LTBP, latent transforming growth factor-β binding protein; MES, mesangial expansion score; SF, skin fibroblast; TGF-β, transforming growth factor-β; TGF-β RII, TGF-β type II receptor.