engleski

The Inflammasome in Cisplatin-Induced AKI

Background: We have demonstrated that there is increased caspase-1, IL-1α, IL-1β and IL-18 in cisplatin (Cis)-induced AKI (CIA). As IL-1α, IL-1β and IL-18 are activated by caspase-1 in the inflammasome, the aim of the study was to further investigate the inflammasome in CIA. The NALP3 inflammasomes is a cytosolic complex consisting NALP3 protein, ASC protein and caspase-5. BID is a pro-apoptotic protein that is secreted by the inflammasome. Methods: Mice were injected with Cis (25 mg/kg) and developed AKI on day 3. ATN was graded as to the number of tubules with histological features of ATN. Results: On immunoblot of whole kidney, there were a 1.3-fold increase in NALP3 on day 2 (P=0.05, n=9) and a 2.6-fold increase in NALP1 (P<0.05, n=9) on day 3 of CIA. On immunoblot, there were a 2-fold increase in ASC on day 2 (P<0.05, n=10), a 3-fold increase in caspase-5 protein on day 2 (P<0.05, n=10), a 2-fold increase in BID on day 2 (P<0.05, n=10), and a 1.2-fold increase in caspase-1 (P<0.05, n=9). As the increase in NALP3 occurred on day 2 at the same time as the increase in ASC, caspase-5, BID and caspase-1, and before the AKI, we considered that inhibition of NALP3 may play an injurious role. To determine whether the increase in NALP3 plays an injurious role in CIA, NALP3-/- mice were studied. Serum creatinine (mg/dL) was 0.22 in vehicle (Veh)-treated, 2.0 in Cis-treated wild type (P< 0.001 vs. Veh, n=10) and 1.2 in Cis- treated NALP3-/- mice (NS vs. wild type, n=9). BUN (mg/dL) was 23 in Veh-treated, 209 in Cis-treated wild type (P< 0.001 vs. Veh, n=10) and 201 in Cis- treated NALP3-/- mice (NS vs. wild type, n=9). ATN score was 1.8 in Cis-treated wild type and 1.5 in Cis-treated NALP3-/- mice (NS vs. wild type, n=5). Apoptosis score (apoptotic cells per 10 HPF) was 8.4 in Cis-treated wild type and 1.4 in Cis- treated NALP3-/- mice (NS vs. wild type, n=5). Conclusions: Inflammasome proteins NALP3, caspase- 1, caspase-5, ASC and BID are increased in whole kidneys on day 2 of CIA. However, NALP3-/- mice are not functionally or histologically protected suggesting that the NALP3 inflammasome does not play an injurious role in CIA. Further investigation of the NALP1 imflammasome is warranted.

Inflammasome; Cisplatin-Induced AKI

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