Cilastatin is an specific inhibitor of Dipeptidase 1 (DPEP1)
Thanks to the research of the scientific founding team of TELARA the MoA of the nephroprotective effect of cilastatin was elucidated and the cholesterol rafts were stablished as one of the main therapeutic targets of non-necrotic death of the proximal cell.
Specifically, it was shown that the pharmacological inhibition of one of the proteins anchored in the raft, Dipeptidase 1 or Dehydropeptidase-I (DPEP1 or DHP-I), by cilastatin blocks the recycling, the endocytosis process and the internalization of the cholesterol rafts, resulting in a reduction or elimination of renal apoptosis induced by toxic agents commonly used in clinical practice (such as chemotherapy agents or antibiotics).
Thanks to the reversal of the changes in the activation states of the “downstream” regulatory proteins of the apoptosis without the elimination or reduction of the pharmacological power of each drug with respect to its therapeutic targets. This finding was also proven for multiple toxic drugs.
Cilastatin blocks the apoptosis process
Figure 1: Effect of cilastatin on gentamicin-induced nephrotoxicity. Administration of gentamicin and cilastatin (200 μg/mL) to PTECS. Left panel: contrasting phase photographs showing cell morphology. Right panel: Confocal microscopy images of the immunolocalization of active caspase-3. Note the reduced cell death and activation of caspase-3 in the presence of cilastatin.
Cilastatin avoids the internalization via cholesterol rafts of the Fas/FasL complex preventing the extrinsic pathway of apoptosis
Figure 2: Summary of the postulated protective mechanism of cilastatin against nephrotoxic-induced AKI. Megalin, an endocytic receptor located in the lipid cholesterol rafts on the apical side of the brush border of renal proximal tubular cells, is the main route of entry and accumulation of substances. In the panel on the left, toxics enter and promote direct tubular damage that affects the mitochondria and the increase in Fas expression that leads (after binding with FasL) to apoptosis and cell death and, finally, to oxidative stress and inflammation, which exacerbate and amplify kidney injury. In the right panel, cilastatin binds to the DPEP1 (DHP-I) membrane of the brush rim in the cholesterol lipid rafts causes a significant reduction in toxicant uptake and nullifies the initial passage of the extrinsic pathway induced by them reducing the activations of caspases 8, 3 and 9, and oxidative and pro-inflammatory signalling pathways, thereby protecting tubular cells.
Cilastatin prevents the extrinsic pathway of apoptosis and the amplification of damage caused by inflammatory and oxidative reactions that chronicize and perpetuate kidney damage.