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 5

Resistance of Pkcd–/– mice and renal tubular cells to cisplatin-induced injury.

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Resistance of Pkcd–/– mice and renal tubular cells to cisplatin-induced ...
(A–D) Wild-type and Pkcd–/– mouse littermates (male, 8–10 weeks of age) were injected with 30 mg/kg cisplatin. (A) Blood samples were collected at days 0, 1, 2, and 3 to measure BUN. At day 3, the animals were sacrificed to collect blood samples (B) to measure serum creatinine and (C and D) to collect kidney tissues for H&E staining and histological analysis and TUNEL assay of apoptosis. Asterisks in D indicate lysed tubules, and arrows indicate TUNEL-positive nuclei. Original magnification, ×200. (E and F) Kidney proximal tubular cells were isolated from wild-type and Pkcd–/– mice for primary culture. The cells were left untreated or treated with 30 μM cisplatin for 20 hours. Apoptosis was evaluated by cell morphology, and caspase activity was measured by enzymatic assay. Mean ± SD, n = 4. *P < 0.001 versus untreated control group; #P < 0.05 versus treated wild-type group.