Nailing down PKC isoform specificity in diabetic nephropathy two's company, three's a crowd

Abstract

Diabetic nephropathy is characterized by early vascu-lar dysfunction and increasing matrix accumulation inthe kidney, eventually leading to proteinuria, glomer-ulosclerosis and interstitial fibrosis [1]. Over the lastdecade, our understanding of the molecular mecha-nisms and the pathogenesis of diabetic nephropathy(and other diabetic microvascular complications) hasbeen greatly enhanced [2]. However, we still do notcompletely understand how metabolic disturbances inthe diabetic state, i.e. hyperglycaemia, induce sucha vast array of distinct cellular events leading toprogressive renal failure [2]. Several hypotheses linkinghyperglycaemia and altered cellular biology have beenproposed [3]. One of these hypotheses postulates thathigh glucose concentration leads to the activation ofthe calcium- and phospholipid-dependent proteinkinase C (PKC) signalling pathway which subse-quently mediates cellular response, e.g. with alteredgene expression [4]. It is generally believed thatintracellular PKC activation is achieved by thediabetes-induced accumulation of one of its co-factors,diacylglycerol (DAG), inside the cell [2,5]. Diabetesmellitus causes elevated DAG levels in vascular tissuesassociated with diabetic complications, includingretina, heart, aorta and renal glomeruli, and in non-vascular tissues such as liver and skeletal muscle [2].However, PKC may also be activated by othermechanisms [6,7]. Oxidative stress has been reportedto induce prolonged activation of PKC within cells [8]through reactive oxygen species (ROS), producedby hyperglycaemia or through ‘advanced glycationend products’ (AGEs) which have been shown todirectly activate PKC [9,10]. Since PKC is animportant intracellular messenger system and plays acentral role in cell proliferation, matrix expression,apoptosis and regulation of gene transcription [4],PKC activation as one of the important underlyingmolecular mechanism of diabetic complications isan attractive hypothesis and a multitude of reportssuggest such a mechanism [4]. Further support comesfrom experimental and human studies, where inhibi-tion of PKC by specific drugs has been shown toprevent early changes in the diabetic retina andkidney [11–16].However, PKC is not a single entity but consists of afamily of at least 12 serine-threonine kinases withdistinct co-factor activation, expression patterns andcellular functions [17]. These isoforms were first clonedin 1986 and have been divided on the basis of theirregulatory domains into three larger subgroups: theclassical (conventional) PKC isoforms a, bI/II and g(regulated by calcium and DAG), the novel PKCisoforms , and (regulated by DAG) and theatypical (non-calcium-/non-DAG-regulated) PKCisoforms and / (Figure 1) [4]. Multiple studiesover the last decade have clearly demonstrated that thevarious PKC isoforms have distinct cellular functionsin different cell types, cellular compartments andsignalling pathways [4,18].