Abstract: TH-OR015
Inhibition of Tubulointerstitial Fibrosis by Targeting the p70 Ribosomal Protein S6 Kinase 1
Session Information
- CKD: Mechanisms of Kidney Fibrosis
October 25, 2018 | Location: 9, San Diego Convention Center
Abstract Time: 05:18 PM - 05:30 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Liu, Ting, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
- Xu, Jinxian, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
- Dai, Caihong, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
- Chen, Jian-Kang, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
Background
Tubulointerstitial fibrosis strongly correlates with the decline of renal function in chronic kidney disease (CKD), regardless of the primary etiology. Tubulointerstitial fibrosis is the major characteristic of the patients with aristolochic acid (AA) nephropathy, which is caused by the ingestion of herbs containing AA. Studies using rapamycin suggested that activation of the target of rapamycin (mTOR) might be causally linked to renal fibrosis, but mTOR knockout caused embryonic lethality; mTOR has multiple downstream effectors, including the p70 S6 kinase 1 (S6K1). Here we report the effect of S6K1 knockout on renal fibrosis.
Methods
Induction of tubulointerstitial fibrosis was accomplished by aristolochic acid I (AAI, given at a dose of 3 mg/kg body weight by daily I.P. for 3 consecutive days) or unilateral urethra obstruction (UUO) in wild type and S6K1 knockout mice. Renal lesions, kidney function and mTOR-S6K1 signaling activities were evaluated.
Results
AAI caused a marked increase of kidney injury molecule 1 (KIM-1) and necrosis of proximal tubular epithelial cells. In addition, we observed that the S2 segment of renal proximal tubule is more susceptible to injury than the S1 and S3 segments of proximal tubule in response to AAI treatment. These lesions resulted in a significant decrease in renal function (indicated by elevated serum creatinine and BUN levels) within 3 days, peaked by day 7. AAI treatment or UUO induced massive tubulointerstitial fibrosis within 2-4 weeks, revealed by a marked reduction of renal tubules, proliferation of a-smooth muscle actin-positive cells, Masson trichrome stains, and deposition of extracellular matrix proteins including fibronectin and fibroblast-specific protein 1 (FSP1). Interestingly, mechanistic studies revealed marked activation of S6K1 and ribosomal protein S6 (rpS6) phosphorylation in the kidney in response to either AAI or UUO. Importantly, mice with global (whole animal) homozygous S6K1 knockout were viable and protected from tubulointerstitial fibrosis.
Conclusion
The present study provides the first unequivocal evidence that activation of S6K1 plays an important pathogenic role during the development of tubulointerstitial fibrosis. Thus, specifically targeting S6K1 may represent a viable strategy for the prevention and treatment of renal fibrosis.
Funding
- NIDDK Support