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Inhibition of protein kinase C in diabetic nephropathy--where do we stand?

Hyperglycaemia plays a key role in the pathogenesis of microvascular diabetic complications. More than 20 years ago, it was described that the activation of the protein kinase C (PKC) system by hyperglycaemia may represent an important mediator of glucotoxicity in diabetic nephropathy [1,2]. The putative intracellular mechanism is the glucoseinduced de novo synthesis of diacylglycerol that is one of the intracellular activators of PKC. Although hyperglycaemia is a major PKC activator, several other PKC stimuli related to the diabetic state such as increased production of reactive oxygen species, free fatty acids or various growth factors and angiotensin II have been identified over the last two decades [3,4] (Figure 1). Thus, inhibition of PKC to prevent complications of diabetes is an attractive hypothesis. However, there are several obstacles to such a strategy. PKC constitutes a family of homologous serine/threonine kinases that are involved in many signalling events [5]. In mammals, a gene family of nine independent gene loci are distributed over the whole genome [6]. Due to biochemical properties and sequence homologies, the PKC family is divided into classical (α, β I, β II, γ), novel (δ, ε, η, θ) and atypical (ζ, ι/λ) isoforms. Despite a similar structure and overlapping substrate specificities in vitro, isoform specificity under in vivo conditions is remarkable and defined via unique expression patterns, intracellular localization and specific binding partners of the isoforms [5,7]. Initially, based on experimental in vitro data, PKCβ was favoured as the main culprit of hyperglycaemia-induced cellular damage [8]. However, soon other PKC isoforms were implicated in the cellular response to hyperglycaemia. The ensuing debate has not been completely resolved; however, recently the analysis of PKC isoform-specific knock-out mice has helped to clarify the role of the different isoforms in diabetic nephropathy [9]. PKCα seems to be important in the regulation of the glomerular barrier and albuminuria. The analysis of PKCα knock-out mice showed that these mice when made hyperglycaemic do not develop albuminuria [10]. Indeed, deletion of PKCα in vivo abolished nephrin loss in STZ-induced murine diabetic nephropathy [11]. Furthermore, PKCα deficiency prevented VEGF upregulation and the loss of negaFig. 1. In the diabetic milieu, metabolic and haemodynamic factors lead to PKC activation and vice versa. Although initiated by the same external stimuli, mainly hyperglycaemia, intracellular signalling cascades activate distinct PKC isoforms each with its own specific role. Thus, PKC isoform specificity and cellular diversity seem to be responsible for the diverge outcome leading to albuminuria and/or renal fibrosis. Importantly, some isoforms, such as PKCε, seem to be protective and should therefore not be medically inhibited. AGE’s: advanced glycation endproducts; RAS: renin–angiotensin system; HSPG: heparin sulphate proteoglycan; VEGF: vascular endothelial growth factor; TGFβ1: transforming growth factor; CTGF: connective tissue growth factor.