Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer
Navjotsingh Pabla, … , Robert O. Messing, Zheng Dong
Navjotsingh Pabla, … , Robert O. Messing, Zheng Dong
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2709-2722. https://doi.org/10.1172/JCI45586.
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Research Article Nephrology

Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

Abstract

Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy.

Authors

Navjotsingh Pabla, Guie Dong, Man Jiang, Shuang Huang, M. Vijay Kumar, Robert O. Messing, Zheng Dong

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Figure 7

Regulation of MAPK by PKCδ during cisplatin nephrotoxicity.

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Regulation of MAPK by PKCδ during cisplatin nephrotoxicity. (A) MAPK act...
(A) MAPK activation during cisplatin nephrotoxicity in wild-type and Pkcd–/– mice. Male wild-type and Pkcd–/– mice of 8 to 10 weeks of age were injected with 30 mg/kg cisplatin. Whole kidney lysates were collected at days 0–3 for immunoblot analysis of phosphorylated and total JNK, ERK, and p38. (B) Cisplatin-induced MAPK activation in primary cultures of wild-type and Pkcd–/– kidney proximal tubular cells. The cells were incubated for 0, 8, 24 hours with 50 μM cisplatin or cisplatin and a MAPK inhibitor (24+I: 5 μM U0126, 10 μM SP600125, or 10 μM SB203580). Whole cell lysates were collected for immunoblot analysis of phosphorylated and total JNK, ERK, and p38. (C and D) Effects of MAPK inhibitors on cisplatin-induced apoptosis in wild-type and Pkcd–/– kidney proximal tubular cells. Kidney proximal tubular cells isolated from (C) wild-type and (D) Pkcd–/– mice were incubated for 24 hours with 50 μM cisplatin in the absence (–) or presence (+) of 5 μM U0126, 10 μM SP600125, or 10 μM SB203580. The percentage of apoptosis was determined by counting the cells with typical apoptotic morphology. Blots in A and B are representatives of at least 3 separate experiments. Mean ± SD, n = 4. *P < 0.001 versus untreated control group; #P < 0.05 versus cisplatin-only group.