Kidney Week

Abstract: SA-PO390

Blocking the Phosphorylation of Ribosomal Protein S6 Inhibits Focal Segmental Glomerulosclerosis

Session Information

• CKD: Risk Factors for Incidence and Progression - III
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 301 CKD: Risk Factors for Incidence and Progression

Authors

• Li, Fang, Fudan University, Shanghai, Shanghai, China

Fang Li,

• Dai, Caihong, Augusta University, Augusta, Georgia, United States

Caihong Dai,

• Zhuang, Qiyuan, Shanghai Medical College, Fudan University, Shanghai, China

Qiyuan Zhuang,

• Chen, Jian-Kang, None, Evans, Georgia, United States

Jian-Kang Chen,

• Wu, Huijuan, Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China

Huijuan Wu,

Background

The pathogenic mechanism of focal segmental glomerulosclerosis (FSGS) remains poorly understood. Renal hypertrophy is largely mediated by phosphorylated rpS6 (p-rpS6), a downstream effector of the mTORC1-S6K1 pathway.

Methods

We detected p-rpS6 levels in kidney biopsy specimens from patients with FSGS. By crossing Tsc1-floxed mice with podocin-Cre mice, we generated podocyte-specific Tsc1 knockout (TSC1^pdKO) mice with or without rapamycin treatment. We also compared Adriamycin (ADR)-induced FSGS, a widely used mouse model of FSGS, in rpS6 knockin mice expressing nonphosphorylatable rpS6 (rpS6^P–/–) and in gender-matched wild type littermates.

Results

p-rpS6 was markedly increased in the renal glomeruli of both FSGS patients and ADR-induced FSGS mice. Podocyte specific rpS6 hyper-phosphorylation induced by genetic deletion of Tsc1, an upstream negative regulator of mTORC1, induced striking hypertrophy of surviving podocytes and recapitulated many features of human FSGS, including podocyte loss and segmental glomerulosclerosis, which were blunted by low-dose rapamycin treatment (0.5 or 1 mg/kg). Similarly, treatment with the phosphatase inhibitor, Tautomycin, also increased p-rpS6 and significantly promoted podocyte hypertrophy, leading to exacerbated FSGS. Conversely, completely blocking rpS6 phosphorylation by generating congenic rpS6 knockin mice expressing non-phosphorylatable rpS6 significantly blunted podocyte hypertrophy and podocyte loss (20% podocytes were lost in rpS6 knockin mice vs. 46% podocytes loss seen in wild type mice) in the ADR-induced mouse model of FSGS. Moreover, pharmacologic inhibition of S6K1 signaling to rpS6 phosphorylation using the S6K1 inhibitor, PF- 4708671, markedly blunted podocyte hypertrophy and attenuated FSGS.

Conclusion

rpS6 hyperphosphorylation plays a key role in adaptive podocyte hypertrophy and progressive podocyte loss in response to initial podocyte injury during the development and progression of FSGS.

Funding

• Private Foundation Support