Abstract: FR-PO606

The Classic and Trans-Signaling of Interleukin-6 Are Both Injurious in Podocyte under High Glucose Exposure

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Lei, Chun-Tao, Huazhong Science and Technology University, Wuhan, China
  • Su, Hua, Huazhong Science and Technology University, Wuhan, China
  • Zhang, Chun, Union Hospital, Huazhong University of Science and Technology, Wuhan Hubei Provicne, China
Background

Interleukin-6 (IL-6) is a multifunctional cytokine that employs IL-6 classic and trans-signaling pathways, and these two signal channels execute different or even opposite effects in certain diseases. As a cardinal event of diabetic kidney disease (DKD), whether the podocyte abnormalities are associated with IL-6 signaling, especially the individual role of IL-6 classic or trans-signaling, remains unclear.

Methods

The circulatory IL-6, soluble IL-6R (sIL-6R) and soluble glycoprotein 130 (sgp130) levels in subjects with or without DKD were measured. Human podocyte cell line was employed in vitro study. RNA interfere targeting gp130 and gp130 or IL-6 neutralizing antibodies were utilized to block the entire IL-6 signaling. RNA interfere targeting IL-6R and recombinant sgp130 were used to inhibit IL-6 classic and trans-signaling respectively.

Results

Our findings elucidated that the circulatory IL-6, sIL-6R and sgp130 levels are elevated in patients with DKD. The expressions of membrane bound IL-6R (mIL-6R), sIL-6R, and gp130 are enhanced in kidney cortex of diabetic mice accompanying with activated STAT3 by tyrosine 705 residue phosphorylation, while not serine 727. Above data infer both classic and trans-signaling of IL-6 are activated during DKD. In cultured podocyte, high glucose (HG) upregulates the expression of mIL-6R and gp130, as well as STAT3 tyrosine 705 phosphorylation, in a time-dependent manner. Entirely blocking IL-6 signaling attenuates HG-induced podocyte injury. Interestingly, either inhibiting IL-6 classic signaling or suppressing its trans-signaling individually also dramatically alleviates HG-induced podocyte injury, suggesting both IL-6 classic and trans-signaling play a detrimental role in HG-induced podocyte injury. Consistently, activation of IL-6 classic or trans-signaling aggravates podocyte damage in vitro.

Conclusion

In summary, our observations demonstrate that either IL-6 classic or trans-signaling aggravates hyperglycemia mediated podocyte impairment. Accordingly, suppressing IL-6 classic and trans-signaling, especially simultaneously, is a promising therapeutic strategy for podocyte injury during DKD.

Funding

  • Government Support - Non-U.S.