Differential activations of PKC/PKA related to microvasculopathy in diabetic GK rats

Abstract

Microvasculopathy is the most serious and predictable threat to the health of diabetic patients, which often results in end-stage renal disease, blindness, and limb amputations. Up to the present, the underlying mechanisms have remained elusive. Here, it was found that the differential activations of PKC/PKA were involved in diabetic microvasculopathy in diabetic GK rats. By real-time PCR, Western blot, immunohistochemistry, and enzyme activity assay, upregulation of PKC was prominent in kidney but was not significant in liver and brain. The expression and activity of PKA were lowered in kidney but comparable in brain and liver during diabetic nephropathy. Furthermore, the generation of reactive oxygen species, production of nitric oxide, and expression of inducible nitric oxide synthase induced by advanced glycation end products were inhibited by PKCβ inhibitor LY-333531 or a PKA agonist in rat glomerular microvascular endothelial cells. Finally, albuminuria was significantly lowered by a PKA agonist and boosted by a PKA antagonist. It suggested that the differential activations of PKC/PKA related to microvasculopathy in diabetes and that activation of PKA may protect the diabetic microvasculature.

Impaired Myogenic Tone in Isolated Cerebral and Coronary Resistance Arteries from the Goto-Kakizaki Rat Model of Type 2 Diabetes

“…This suggests the presence of a defect in the agonist-induced signaling in the coronary arteries which is not mediated by the Rho-kinase pathway. Possible candidates for these defects could include diabetes-induced alterations in the PKA [36] and the PKC [37,38] pathways as recently shown for isolated glomeruli, but not for brain and liver microvessels, in 9-month-old GK rats [24]. These findings could possibly support our finding of similar agonist-induced responses in cerebral arteries from GK and CW rats.…”

“…The vascular abnormalities seen in diabetes are far from being fully characterized, possibly because they not only differ with the duration, severity and type of diabetes, but also may differ within the different vascular beds from the same individual [23,24]. The mechanism underlying diabetes-induced alterations of myogenic responses are also unclear.…”

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

“…Recently, we have found that PKA activity is also closely correlated with the occurrence of diabetic nephropathy. The use of a PKA agonist can control or improve diabetic nephropathy (Wang et al 2012).…”

“…Diabetic rats were then fed conventional chow for an additional 10 weeks and 24 h urinary albumin was determined. When the 24 h urinary albumin level was O400 mg, the establishment of a diabetic nephropathy animal model was confirmed (Wang et al 2012). A total of 18 GK rats with diabetic nephropathy were divided into three groups, according to a random number table (nZ6 in each group), as follows.…”

“…PKC activity is increased and PKA activity is decreased in diabetic nephropathy, thus the PKC/PKA balance is disturbed. Treatment with a PKA agonist may also effectively prevent and/or treat diabetic nephropathy (Wang et al 2012).…”