Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes

Wang, J.; Casimiro-Garcia, A.; Johnson, B. G.; Duffen, J.; Cain, M.; Savary, L.; Wang, S.; Nambiar, P.; Lech, M.; Zhao, S.; Xi, L.; Zhan, Y.; Olson, J.; Stejskal, J. A.; Lin, H.; Zhang, B.; Martinez, R.; Masek-Hammerman, K.; Schlerman, F. J.; Dower, K.

doi:10.1101/2020.12.02.406892

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bioRxiv · 10.1101/2020.12.02.406892

Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes

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Abstract

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects of T2D, for many patients these approaches do not sufficiently control the disease. As a result, an emerging therapeutic strategy is to target the pathobiological mechanisms downstream of T2D metabolic derangement that can result in organ damage, morbidity, and mortality in afflicted individuals. One such proposed mechanism involves the Protein Kinase C (PKC) family members PKC and PKC{beta}, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKC and PKC{beta} in the context of T2D, we have evaluated a potent and orally bioavailable inhibitor, herein referred to as Cmpd 1, in the ZSF1 rat model of leptin-receptor deficiency, obesity-driven T2D. Therapeutic dosing of Cmpd 1 virtually halted renal function decline but did so indirectly by blunting the hyperphagia response of these animals. Beyond this clear but indirect effect, Cmpd 1 had direct and prominent effects on body weight and in liver and inguinal white adipose tissue (iWAT) when administered to ZSF1 obese rats.

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Wang, J., Casimiro-Garcia, A., Johnson, B. G., Duffen, J., Cain, M., Savary, L., Wang, S., Nambiar, P., Lech, M., Zhao, S., Xi, L., Zhan, Y., Olson, J., Stejskal, J. A., Lin, H., Zhang, B., Martinez, R., Masek-Hammerman, K., Schlerman, F. J., Dower, K.. 2020-12-03. Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes. https://doi.org/10.1101/2020.12.02.406892

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