Tandem Inhibition of PKC in Diαβetic Nephropathy

It Takes Two to Tango?

  1. Mark E. Cooper1,2,3
  1. 1Diabetes Complications Division, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
  2. 2Department of Medicine, Austin and Northern Clinical Schools, University of Melbourne, Victoria, Australia
  3. 3Department of Medicine and Immunology, Alfred Medical Research & Education Precinct, Monash University, Melbourne, Australia
  1. Corresponding author: Mark E. Cooper, mark.cooper{at}bakeridi.edu.au.

It is now more than 15 years since the initial reports of upregulation of protein kinase C (PKC) isoforms in the diabetic kidney and positive preclinical data with the PKC isoform inhibitor, ruboxistaurin. However, subsequent clinical studies with ruboxistaurin that failed to reach key primary end points and the failure of the PKC-α or PKC-β isoform knockout mice in the presence of diabetes to totally prevent the diabetes-associated renal lesions have reduced the enthusiasm for targeting PKC isoforms in diabetic nephropathy. However, as reported in this issue of Diabetes, Menne et al. (1) have provided positive provocative data suggesting that dual inhibition of PKC-α and -β isoforms is a novel approach that warrants consideration in diabetic nephropathy. The work is strengthened by using not only a genetic approach, i.e., a double PKC isoform knockout mouse, but by also using a PKC-α/β inhibitor, albeit its specificity remains questionable.

PKC has been implicated in the pathogenesis of diabetic nephropathy. PKC is a family of closely related enzymes that phosphorylate serine or threonine residues of various intracellular proteins and thus is involved in a wide range of cellular functions that may be relevant to the pathophysiology of diabetes complications including basement membrane production and signal transduction for hormones and growth factors (2). At least 11 isoforms have been identified and classified into three groups. The first group is the conventional PKCs, including the isoforms studied by Menne et al. …

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