TSC1 deletion in fibroblasts alleviates lipopolysaccharide-induced acute kidney injury

Mechanistic target of rapamycin complex 1 (mTORC1) signaling is active in inflammation, but its involvement in septic acute kidney injury (AKI) has not been shown. mTORC1 activation (p-S6) in renal fibroblasts was increased in a mouse AKI model induced by 1.5 mg/kg lipopolysaccharide (LPS). Deletion of TSC1, an mTORC1 negative regulator, in fibroblasts (Fibro-TSC1–/–) inhibited the elevation of serum creatinine and blood urea nitrogen in AKI compared with that in TSC1fl/fl control mice. Endothelin-1 and p-JNK were upregulated in Fibro-TSC1–/– renal fibroblasts after LPS challenge. Rapamycin, an mTORC1 inhibitor, and bosentan, an endothelin-1 antagonist, eliminated the difference in renal function between TSC1fl/fl and Fibro-TSC1–/– mice after LPS injection. Rapamycin restored LPS-induced upregulation of endothelin-1, endothelin converting enzyme-1 (ECE1), and p-JNK in TSC1-knockdown mouse embryonic fibroblasts (MEFs). SP600125, a JNK inhibitor, attenuated LPS-induced enhancement of endothelin-1 and ECE1 in TSC1-knockdown MEFs without a change in p-S6 level. The results indicate that mTORC1-JNK-dependent upregulation of ECE1 elevated endothelin-1 in TSC1-knockout renal fibroblasts and contributed to improvement of renal function in Fibro-TSC1–/– mice with LPS-induced AKI. Renal fibroblast mTORC1 plays an important role in septic AKI.

Source: Clinical Science - September 5, 2018 Category: Biomedical Science Authors: Shen, J., Cui, Z.-K., Yao, F., Li, K., Zhang, Y., Chen, Z., Zhou, Y., Xu, S., Zhang, Y., Jiang, W., Zhang, H., Tan, K., Liu, A., Bai, X. Tags: PublishAheadOfPrint Source Type: research