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

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-beta 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-kappa B pathway. GDF-15 and other proinflammatory factors, such as TNF-alpha, IL-1 beta, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF15 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-kappa B through IKK and I kappa B alpha 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-kappa B and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.