Cilastatin, a new therapeutic alternative for acute renal injury
Cilastatin is a specific competitive blocker of renal dehydropeptidase I (DHP-I) enzyme which is located on brush-border cholesterol rafts of renal tubular cells.
Cilastatin has been extensively used in combination with the antibiotic imipenem (Primaxin®, Tienam®) since 1985. Therefore, the efficacy and safety of this combination product in humans is well known ever since and still is being used in the clinical setting.
Our preclinical in vitro and in vivo studies have demonstrated that cilastatin protects the kidney against tubular cell injury and acute kidney injury (AKI) caused by nephrotoxic drugs such as cisplatin, cyclosporine and gentamicin, and other non-toxic conditions such as sepsis.
The binding of cilastatin to DHP-I produces an interruption of cholesterol raft internalization and a reduction in membrane turnover, with two main effects:
- Decreased nephrotoxic compounds uptake.
- Reduction or cancellation of signaling pathway by death receptors.
Specifically, cilastatin prevents internalization, trimerization and signaling through the Fas/Fas ligand complex.
The result is the prevention of programmed cell death and the subsequent damage expansion phase by inhibiting oxidative and inflammatory amplifying cascade of cell damage.