Protein kinase C activation and its role in kidney disease

Protein kinase C (PKC) comprises a superfamily of isoenzymes, many of which are activated by cofactors such as diacylglycerol and phosphatidylserine. In order to be capable of activation, PKC must first undergo a series of phosphorylations. In turn, activated PKC phosphorylates a wide variety of intracellular target proteins and has multiple functions in signal transduced cellular regulation. A role for PKC activation had been noted in several renal diseases, but two that have had most investigation are diabetic nephropathy and kidney cancer. In diabetic nephropathy, an elevation in diacylglycerol and/or other cofactor stimulants leads to an increase in activity of certain PKC isoforms, changes that are linked to the development of dysfunctional vasculature. The ability of isoform-specific PKC inhibitors to antagonize diabetes-induced vascular disease is a new avenue for treatment of this disorder. In the development and progressive invasiveness of kidney cancer, increased activity of several specific isoforms of PKC has been noted. It is thought that this may promote the kidney cancer's inherent resistance to apoptosis, in natural regression or after treatments, or it may promote the invasiveness of renal cancers via cellular differentiation pathways. In general, however, a more complete understanding of the functions of individual PKC isoforms in the kidney, and development or recognition of specific inhibitors or promoters of their activation, will be necessary to apply this knowledge for treatment of cellular dysregulation in renal disease.

In vivo demonstration of load-induced fluid flow in the rat tibia and its potential implications for processes associated with functional adaptation

Load-induced extravascular fluid flow has been postulated to play a role in mechanotransduction of physiological loads at the cellular level. Furthermore, the displaced fluid serves as a carrier for metabolites, nutrients, mineral precursors and osteotropic agents important for cellular activity. We hypothesise that load-induced fluid flow enhances the transport of these key substances, thus helping to regulate cellular activity associated with processes of functional adaptation and remodelling. To test this hypothesis, molecular tracer methods developed previously by our group were applied in vivo to observe and quantify the effects of load-induced fluid flow under four-point-bending loads. Preterminal tracer transport studies were carried out on 24 skeletally mature Sprague Dawley rats. Mechanical loading enhanced the transport of both small- and larger-molecular-mass tracers within the bony tissue of the tibial mid-diaphysis. Mechanical loading showed a highly significant effect on the number of periosteocytic spaces exhibiting tracer within the cross section of each bone. For all loading rates studied, the concentration of Procion Red tracer was consistently higher in the tibia subjected to pure bending loads than in the unloaded, contralateral tibia, Furthermore, the enhancement of transport was highly site-specific. In bones subjected to pure bending loads, a greater number of periosteocytic spaces exhibited the presence of tracer in the tension band of the cross section than in the compression band; this may reflect the higher strains induced in the tension band compared with the compression band within the mid-diaphysis of the rat tibia. Regardless of loading mode, the mean difference between the loaded side and the unloaded contralateral control side decreased with increasing loading frequency. Whether this reflects the length of exposure to the tracer or specific frequency effects cannot be determined by this set of experiments. These in vivo experimental results corroborate those of previous ex vivo and in vitro studies, Strain-related differences in tracer distribution provide support for the hypothesis that load-induced fluid flow plays a regulatory role in processes associated with functional adaptation.