Sirolimus Prevents Short-Term Renal Changes Induced by Ischemia-Reperfusion Injury in Rats

Abstract

Background: Ischemia-reperfusion (I/R) is present at various degrees in kidney transplants. I/R plays a major role in early function and long-term survival of renal allograft. The purpose of our study was to determine if immunosuppressants modulate I/R in a model that separates I/R from all immune responses. Methods: Sprague-Dawley rats with monolateral renal I/R received daily cyclosporine (A), tacrolimus (B), sirolimus (C) or saline (D). Sham-operated rats received saline (E). After 30 days, glomerular filtration rate for each kidney was measured by inulin clearance. Kidney injury was examined, and TGF-β, fibronectin and metalloproteases were evaluated by real-time PCR, Western blot and zymography. Results: Sirolimus, but not cyclosporine and tacrolimus, prevented a glomerular filtration rate decrease in I/R kidneys (403 ± 303 vs. 1,006 ± 484 µl/min, p < 0.05; 126 ± 170 vs. 567 ± 374 µl/min, p < 0.05; 633 ± 293 vs. 786 ± 255; A, B and C group, respectively, I/R vs. contralateral kidneys). Sirolimus reduced ED-1+ cell infiltrate, interstitial fibrosis and intimal thickening of small vessels observed in I/R kidneys of controls and calcineurin inhibitor-treated rats. Tacrolimus and cyclosporine increased fibronectin and TGF-β expression and matrix deposition. Only sirolimus increased metalloprotease activity. Conclusions: Sirolimus but not calcineurin inhibitors prevented I/R-induced kidney injury.

Predictive Usefulness of Urinary Biomarkers for the Identification of Cyclosporine A-Induced Nephrotoxicity in a Rat Model

“…Its overexpression occurs in experimental and clinical acute tubular injury [44]–[45] and in models of CsA-induced nephrotoxicity [28]–[29]. The early increase in the urinary excretion and renal tissue overexpression of fibronectin observed in this study were most likely associated with tubular injury resulting directly from CsA toxicity to renal tubular cells or CsA-induced renal ischemia.…”

The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis

“…Among the methods tested for attenuation of renal IRI are many drugs [22,23], endocrine hormones [24], erythropoietin [21], and small interfering RNA [25]. Various drawbacks, however, have prevented their clinical application.…”

Effects of Everolimus on Oxidative Stress in Kidney Model of Ischemia/Reperfusion Injury

“…Similar effects have been reported in the work of Lieberthal et al [27], who found no differences in kidney function on day 7 after induced IRI between non-treated and rapamycin-treated rats, but by day 6 after induced IRI, rapamycin-treated animals had lower GFR and worse histology score. It is important to note that when renal function was explored 30 days after induced renal IRI in rats, it was found that rapamycin prevented GFR decline [28]. …”