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

• DOI: 10.1101/2020.12.02.406892
• Publication Date: 2020-12-04T05:30:14Z
• Authors: Ju Wang; Agustin Casimiro-...; Bryce G. Johnson; Jennifer Duffen; Michael Cain; Leigh Savary; Stephen Wang; Prashant Nambiar; Matthew Lech; Shanrong Zhao; Li Xi; Yutian Zhan; Jennifer Olson; James A. Stejskal; Hank Lin; Baohong Zhang; Robert V. Martinez; Katherine Masek-H...; Franklin J. Schle...; Ken Dower
• Keywords: 0301 basic medicine; 2. Zero hunger; 03 medical and health sciences; 3. Good health

AbstractType 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 PKCα and PKCβ, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKCα and PKCβ 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.