Functional and histopathologic effects of rapamycin on mouse kidney

Area of Science:

• Nephrology
• Pharmacology
• Toxicology

Background:

• Kidney function and histopathology are critical parameters in drug safety assessment.
• Rapamycin (RAPA) and Cyclosporine (CsA) are immunosuppressive drugs with known nephrotoxic potential.
• Understanding the comparative renal effects of RAPA and CsA is crucial for clinical application.

Purpose of the Study:

• To evaluate the impact of Rapamycin (RAPA) on kidney function and histopathology in different mouse strains.
• To compare the nephrotoxic profile of RAPA with that of Cyclosporine (CsA) in mice.
• To determine the therapeutic index of RAPA relative to CsA in preclinical models.

Main Methods:

• Two mouse strains (C3H/HeJ and Balb/cJ) were administered varying doses of RAPA via intraperitoneal injection over 4 or 7 days.
• Female Balb/cJ mice received Cyclosporine (CsA) at escalating doses (50-200 mg/kg) for 7 days.
• Kidney function was assessed by blood urea nitrogen (BUN) levels, and kidney histopathology was examined for drug-induced changes.

Main Results:

• Rapamycin (RAPA) caused transient BUN elevations not consistently dose-dependent and absent in high-dose, 7-day studies.
• Body weight depression occurred in 7-day RAPA studies; proximal tubule vacuolization was observed at high doses.
• Cyclosporine (CsA) induced significant mortality at high doses (150-200 mg/kg) and elevated BUN at 100 mg/kg.

Conclusions:

• Rapamycin (RAPA) exhibited minimal adverse effects on kidney function and structure in mice, even at doses significantly exceeding therapeutic levels.
• RAPA demonstrated a superior therapeutic index compared to Cyclosporine (CsA) in this preclinical mouse model.
• These findings suggest RAPA may offer a safer alternative to CsA with reduced nephrotoxicity risk.