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Updated: Feb 11, 2026
Direct Drug Delivery to Kidney via the Renal Artery
Published on: April 17, 2021
GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure
Marianne Pons1, Leonidas G Koniaris1, Sharon M Moe2
1Department of Surgery, Indiana University School of Medicine, Indianapolis.
Background:
GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases.
Methods:
In vitro renal cell lines, genetic, and murine in vivo renal injury models were examined.
Results:
Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely after 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, or unilateral ureteric obstruction. Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis, and expression of fibrosis-associated genes both at baseline and after unilateral ureteric obstruction compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted epithelial-to-mesenchymal transition of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner.
Conclusion:
Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function.
Insights
Growth Differentiation Factor 11 (GDF11) plays a key role in adult kidney injury and fibrosis. High doses cause renal failure, while reduced GDF11 protects against kidney disease, suggesting GDF11 as a therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Developmental Biology
Background:
- Growth Differentiation Factor 11 (GDF11) is known to modulate embryonic development and kidney organogenesis.
- The precise function of GDF11 in the adult kidney and its role in renal diseases remain to be fully elucidated.
Purpose of the Study:
- To define the function of GDF11 in the adult kidney.
- To investigate the role of GDF11 in the context of renal injury and disease.
Main Methods:
- Utilized in vitro renal cell lines and genetic approaches.
- Employed murine in vivo models of renal injury, including 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, and unilateral ureteric obstruction.
- Administered systemic high-dose GDF11 and analyzed Gdf11 heterozygous mice.
Main Results:
- Gdf11 expression is highest in normal adult mouse kidneys and increases following acute kidney injury.
- Systemic administration of high-dose GDF11 induced renal failure, atrophy, interstitial fibrosis, and epithelial-to-mesenchymal transition in mice.
- Gdf11 heterozygous mice exhibited reduced renal fibrosis and associated gene expression compared to wild-type littermates.
- GDF11 directly induced proliferation and activation of renal fibroblasts and epithelial-to-mesenchymal transition in renal tubular cells via SMAD signaling.
Conclusions:
- GDF11 and its downstream signaling pathways are critical in vivo mediators of renal injury and fibrosis.
- GDF11 exerts direct effects on renal tubular cells and fibroblasts, contributing to kidney damage.
- Modulating GDF11 presents a potential therapeutic strategy for diseases characterized by renal fibrosis and impaired tubular function.
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