GDF-15 alleviates diabetic nephropathy via inhibiting NEDD4L-mediated IKK/NF-κB signalling pathways.

Abstract

Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-β superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1β, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.

• Authors: Xinyu Zhang, Simeng Wang, Nannan Chong, Dandan Chen, Jianqiang Shu, Jingshu Sun, Zhikang Sun, Rong Wang, Qinglian Wang, Ying Xu
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 128 Pg. 111427 (Feb 15 2024) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 38181673 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Growth Differentiation Factor 15
• NF-kappa B
• Ubiquitins

Topics

• Animals
• Rats
• Diabetic Nephropathies (drug therapy, metabolism)
• Growth Differentiation Factor 15 (metabolism)
• Inflammation (metabolism)
• NF-kappa B (metabolism)
• Podocytes (metabolism)
• Ubiquitins (metabolism, therapeutic use)