Mediators of Diabetic Renal Disease: The Case for TGF-β as the Major Mediator
Abstract
The critical role of hyperglycemia in the genesis of diabetic nephropathy has been established by cell culture studies, experimental animal models, and clinical trials. Certain cytokines and growth factors have been identified as likely mediators of the effects of high ambient glucose on the kidney, but prominent among these is TGF-beta, a prototypical hypertrophic and fibrogenic cytokine. Overexpression of TGF-beta has been demonstrated in the glomerular and tubulointerstitial compartments of experimental diabetic animals. The TGF-beta receptor signaling system is also triggered, as evidenced by upregulation of the TGF-beta type II receptor and activation of the downstream Smad signaling pathway. Treatment of diabetic mice with neutralizing anti-TGF-beta antibodies prevents the development of renal hypertrophy, mesangial matrix expansion, and the decline in renal function. Antibody therapy also reverses the established lesions of diabetic glomerulopathy. These studies argue strongly in support of the hypothesis that overactivity of the TGF-beta system in the kidney is a crucial mediator of diabetic renal hypertrophy and mesangial matrix expansion.
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Fibrosis is a key pathological hallmark of DKD, and a major role has been identified for prosclerotic growth factors such as TGF-β.
“Fibrosis is a key pathological hallmark of DKD, and a major role has been identified for prosclerotic growth factors such as TGF-β (68).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [68]
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“Fibrosis is a key pathological hallmark of DKD, and a major role has been identified for prosclerotic growth factors such as TGF-β (68).”
Kugathasan, L., Aronson, Y., Sridhar, V. S., Ni, H., Ouimet, J.-P., Limonte, C. P., Sarma, S., & Cherney, D. Z. I. (2025) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2025.2537446 · Cited by 9 · see citing works
- Authors
- Ziyadeh, F. N.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Ziyadeh, Fuad N.
- Venue
- Journal of the American Society of Nephrology
- Published
- 2004-01
- Volume
- 15
- Issue
- 1_suppl
- Pages
- S55-S57
- ISSN
- 1046-6673 (ISSN-L)
- OpenAlex
- W2101051256
- Cited by
- 463
- References
- 0
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 10 · 2022: 14 · 2021: 12 · 2020: 18 · 2019: 13 · 2018: 14 · 2017: 18 · 2016: 29 · 2015: 28 · 2014: 39 · 2013: 26 · 2012: 32
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health
- National Institutes of Health (5r01dk054608-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 44513, P50DK045191, DK-45191, DK-54608, R01DK044513)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- diabetic nephropathy, hyperglycemia, TGF-beta, TGFBR2, Smad signaling, renal hypertrophy, mesangial expansion, glomerular fibrosis, tubulointerstitial fibrosis, cytokines and growth factors
- MeSH terms
- Diabetic Nephropathies, Humans, Kidney, Up-Regulation, Transforming Growth Factor beta
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