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Sirolimus damages podocytes in rats with protein overload nephropathy
Yong Cai1, Yan Chen, Shaoling Zheng
1Department of Renal Transplantation, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou - PR China. yorkcai@126.com
Background:
Conversion from calcineurin inhibitors (CNIs) to sirolimus could significantly improve long-term graft survival after kidney transplantation. Proteinuria was found in some recipients after the switch, which could be alleviated by an angiotensin II receptor blocker (ARB). But the mechanisms for this have remained unclear. In this study, we utilized a rat model with protein overload nephropathy to explore the mechanisms of sirolimus-related proteinuria.
Methods:
A rat model with protein overload nephropathy was induced by repeated injections of bovine serum albumin. Model rats also received sirolimus (rapamycin) treatment or ARB agent (losartan) pretreatment. Urinary protein excretion from 24-hour urine specimens was calculated, and the morphological changes of renal tissues were analyzed by hematoxylin and eosin staining and electron microscopy. The expression of desmin, a sensitive marker of podocyte injury, was detected by immunohistochemical staining.
Results:
Rapamycin increased urinary protein excretion and intratubular protein cast formation in rats with protein overload nephropathy. The foot process effacement of podocytes was found by electron microscopy after rapamycin treatment. The expression of desmin was up-regulated after rapamycin treatment. However, losartan pretreatment could attenuate proteinuria in spite of rapamycin treatment.
Conclusion:
Sirolimus aggravates proteinuria in rats with protein overload nephropathy by damaging podocytes, a barrier of glomerular filtration. Furthermore, angiotensin II receptor blocker can counteract the effect of sirolimus, not only through hemodynamic changes but also partly by repairing the injury of podocytes. This study might be useful for understanding the mechanism of sirolimus-related proteinuria and guiding clinical treatments.
Insights
Sirolimus worsens proteinuria in kidney transplant rats by damaging podocytes. Angiotensin II receptor blockers (ARBs) counteract this effect, offering potential clinical benefits for managing sirolimus-related proteinuria.
Area of Science:
- Nephrology
- Pharmacology
- Immunology
Background:
- Conversion from calcineurin inhibitors (CNIs) to sirolimus can improve kidney graft survival.
- Sirolimus use is associated with proteinuria, which can be managed by angiotensin II receptor blockers (ARBs).
- The precise mechanisms underlying sirolimus-related proteinuria remain unclear.
Purpose of the Study:
- To investigate the mechanisms by which sirolimus induces proteinuria in a rat model.
- To explore the protective effects of ARBs against sirolimus-induced proteinuria.
Main Methods:
- A rat model of protein overload nephropathy was established using bovine serum albumin injections.
- Rats were treated with sirolimus (rapamycin) or pretreated with an ARB (losartan).
- Urinary protein excretion, renal tissue morphology (H&E, electron microscopy), and podocyte injury marker (desmin) expression were assessed.
Main Results:
- Sirolimus administration significantly increased proteinuria and intratubular protein cast formation.
- Electron microscopy revealed podocyte foot process effacement and increased desmin expression after sirolimus treatment.
- Losartan pretreatment effectively attenuated proteinuria despite ongoing sirolimus treatment.
Conclusions:
- Sirolimus exacerbates proteinuria in protein overload nephropathy by directly damaging podocytes, crucial for glomerular filtration.
- Angiotensin II receptor blockers counteract sirolimus-induced proteinuria through hemodynamic effects and direct podocyte injury repair.
- Findings provide insights into sirolimus-related proteinuria mechanisms and guide clinical management strategies.
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