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

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

  • Int Immunopharmacol. 2024 Jan 4:128:111427. doi: 10.1016/j.intimp.2023.111427.
Xinyu Zhang 1,  Simeng Wang 1,  Nannan Chong 2,  Dandan Chen 1,  Jianqiang Shu 1,  Jingshu Sun 3,  Zhikang Sun 2,  Rong Wang 4,  Qinglian Wang 5,  Ying Xu 6
Affiliations

Affiliations

  • 1 Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
  • 2 Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 3 Department of Nephrology, Weifang People's Hospital, Weifang, Shandong, China.
  • 4 Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China; Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 5 Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China; Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: 15216401100@163.com.
  • 6 Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China; Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: 15562450030@163.com.
PMID: 38181673 DOI: 10.1016/j.intimp.2023.111427
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.

Keywords

Diabetic nephropathy; GDF-15; Inflammation; NEDD4L; Ubiquitin.

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