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Abstract: TH-PO904

The Effect of A1AR on Diabetic Megalin Loss-Associated Albuminuria by Inhibiting Caspase-1/IL18 Signaling

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Tian, Dongli, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Shi, Xiaoxiao, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Zou, Linfeng, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Wen, Yubing, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Chen, Limeng, Peking Union Medical College Hospital, Beijing, BEIJING, China
Background

The mechanism of exacerbation of albuminuria observed in A1 adenosine receptor knock-out (A1AR-/-)mice with diabetic nephropathy (DN) is unclear. Here, we investigated the relationship of megalin loss and albuminuria, to identify the effect of A1AR in the pyroptosis signaling caspase-1/IL-18 of DN.

Methods

Successfully collected diabetic nephropathy patients’ samples and built streptozotocin-induced diabetes mice model. Megalin, cubilin, and A1AR expression were detected in kidney tissue samples from DN patients and mice through immunohistochemical and immunofluorescent staining. A1AR, caspase-1, Interleukin -18 (IL-18) expression were analyzed using western blotting in wild-type and A1AR-/- mice. Human renal proximal tubular epithelial cells (PTC) were cultured with high glucose to observe the effect of A1AR agonist and antagonist on caspase-1/IL-18 and megalin injury.

Results

The loss of megalin, co-localized with A1AR at PTC, was associated with the level of albuminuria in diabetic patients and mice. The injury of megalin-cubilin was accompanied by the A1AR upregulation and the caspase-1/IL-18 signaling activation in mice with DN. More severe pathological injury, albuminuria, and megalin-cubilin loss were observed in A1AR-/- DN mice with more pronounced caspase-1 and IL-18 secretion. High glucose could stimulate the secretion of caspase-1 and IL-18, which was completely abolished by A1AR agonist and further aggravated by A1AR antagonist.

Conclusion

A1AR played an important role in protecting megalin loss associated albuminuria by inhibiting the pyroptosis signaling caspase-1/IL-18 in DN.

Funding

  • Government Support - Non-U.S.