Related Experiment Video
Updated: Jun 8, 2026
Development and Application of Rapamycin-regulated Tyrosine Phosphatases
Published on: September 6, 2024
mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease
Franck Belibi1, Kameswaran Ravichandran, Iram Zafar
1Division of Renal Diseases and Hypertension, University of Colorado at Denver and Health Sciences Center, Box C281, 12700 East 19th Ave., Aurora, CO 80262, USA.
Abstract:
Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.
Insights
Rapamycin did not slow polycystic kidney disease (PKD) in female rats, despite affecting mTORC1 and mTORC2 signaling pathways. This contrasts with effects seen in male rats, indicating sex-specific responses to rapamycin in PKD.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Polycystic kidney disease (PKD) is a genetic disorder characterized by cyst formation in the kidneys.
- Rapamycin has shown efficacy in slowing PKD progression in male Han:SPRD (Cy/+) rats.
- The roles of mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in PKD pathogenesis and rapamycin response are not fully understood, particularly in females.
Purpose of the Study:
- To investigate the effect of rapamycin on PKD in female Cy/+ rats.
- To determine the involvement of mTORC1 and mTORC2 signaling pathways in female rats with PKD treated with rapamycin.
- To compare the effects of rapamycin on PKD and related signaling pathways between female and male Cy/+ rats.
Main Methods:
- Female Cy/+ rats were treated with rapamycin from 4 to 12 weeks of age.
- Kidney volume, cyst volume density (CVD), and cell proliferation (PCNA) and apoptosis (caspase-3, TUNEL) markers were assessed.
- Activity of mTORC1 (p-S6) and mTORC2 (p-Akt Ser473, p-PKCα Ser657) signaling pathways were analyzed via immunoblotting.
Main Results:
- Rapamycin treatment did not alter kidney size, CVD, or cellular proliferation/apoptosis in female Cy/+ rats.
- mTORC1 activity marker (p-S6) was reduced by rapamycin, but mTORC2 activity marker (p-Akt Ser473) was increased in female Cy/+ rats.
- In contrast, rapamycin decreased p-Akt (Ser473) in male Cy/+ rats, where it effectively slowed PKD progression.
Conclusions:
- Rapamycin is ineffective in reducing PKD progression in female Cy/+ rats.
- The lack of efficacy may be linked to rapamycin-induced activation of mTORC2 signaling (p-Akt Ser473) in females.
- Sex-specific differential regulation of mTORC2 signaling pathways influences rapamycin's therapeutic effect in polycystic kidney disease.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...