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 6

Independent regulation of p53 and PKCδ during cisplatin nephrotoxicity.

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Independent regulation of p53 and PKCδ during cisplatin nephrotoxicity. ...
(A) Cisplatin-induced p53 activation in kidney tissues. Wild-type and Pkcd–/– mice were injected with 30 mg/kg cisplatin before collection of whole kidney lysates for immunoblotting. (B) Cisplatin-induced p53 activation in primary Pkcd–/– kidney tubular cells. The cells were incubated with 50 μM cisplatin for 24 hours to collect lysate for immunoblotting. (C) Cisplatin-induced PKCδ activation in kidney tissues. Wild-type and p53–/– mice were injected with 30 mg/kg cisplatin before collection of whole kidney lysates for immunoblotting. (D) Cisplatin-induced PKCδ activation in primary p53–/– kidney tubular cells. The cells were incubated for 24 hours with 50 μM cisplatin to collect lysate for immunoblotting. (E) Effects of pifithrin-α and rottlerin on cisplatin-induced apoptosis in primary Pkcd–/– kidney tubular cells. The cells were treated for 24 hours with 50 μM cisplatin in the absence or presence of 10 μM rottlerin or 20 μM pifithrin-α to determine the percentage of apoptosis by morphological methods. (F) Effects of pifithrin-α and rottlerin on cisplatin-induced apoptosis in primary wild-type and p53–/– kidney tubular cells. The cells were treated for 24 hours with 50 μM cisplatin in the absence or presence of 10 μM rottlerin or 20 μM pifithrin-α to determine the percentage of apoptosis by morphological methods. Mean ± SD, n = 4. #P < 0.05 versus the cisplatin group of the same genotype cells.