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Wilkinson-Berka J.L.,Baker International Diabetes Institute Heart and Diabetes Research Institute | Heine R.,Baker International Diabetes Institute Heart and Diabetes Research Institute | Tan G.,Baker International Diabetes Institute Heart and Diabetes Research Institute | Cooper M.E.,Monash University | And 5 more authors.
Hypertension | Year: 2010

The (pro)renin receptor [(P)RR] is implicated in organ pathology. We examined the cellular location of the (P)RR and whether a putative (P)RR antagonist, RILLKKMPSV, corresponding to the handle region of the prorenin prosegment (handle region peptide [HRP]) influences angiogenesis, inflammation, and neuronal and glial function in rat retina. The (P)RR was localized to retinal vessels, endothelial cells, and pericytes, but most immunolabeling was in ganglion cells and glia. HRP (1 mg/kg per day by IP injection) reduced physiological angiogenesis in developing retina. Moreover, HRP (0.1 mg/kg per day by subcutaneous minipump) reduced pathological retinal angiogenesis, inflammation, and vascular endothelial growth factor and intercellular adhesion molecule-1 mRNA in rats with oxygen-induced retinopathy (OIR) to an extent similar to valsartan (10 mg/kg per day, IP). In contrast to its effects on vasculature, HRP compromised the electroretinogram in shams and OIR and increased phosphorylated extracellular-signal-related protein kinase 1/2 immunolabeling in shams but not in OIR, whereas valsartan did not affect the electroretinogram and reduced extracellular-signal-related protein kinase 1/2 immunolabeling in OIR. Retinal (P)RR mRNA levels were increased in OIR; HRP, but not valsartan, increased (P)RR mRNA levels in shams, whereas both HRP and valsartan reduced (P)RR mRNA levels in OIR. A control peptide (VSPMKKLLIR, 0.1 mg/kg per day) did not influence retinal vasculopathy or function. Circulating HRP levels in rats administered 1 mg/kg per day HRP were undetectable (<3 pmol/L). We conclude that HRP had protective effects on the retinal vasculature similar to those of valsartan; however, unlike valsartan, HRP injured neuro-glia, which may involve the (P)RR, although the undetectable circulating HRP level makes a direct effect of HRP on retinal (P)RR function unlikely. © 2010 American Heart Association, Inc.


Tan A.L.Y.,Baker International Diabetes Institute Heart and Diabetes Research Institute | Tan A.L.Y.,University of Melbourne | Sourris K.C.,Baker International Diabetes Institute Heart and Diabetes Research Institute | Harcourt B.E.,Baker International Diabetes Institute Heart and Diabetes Research Institute | And 12 more authors.
American Journal of Physiology - Renal Physiology | Year: 2010

Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE-/-) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE-/- mice were protected against albuminuria, hyper-filtration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide. Whereas glomerulosclerosis, tubulointerstitial expansion, and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE-/- and alagebrium-treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (carboxymethyllysine) levels. Low-AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression, or improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, diverse approaches to block the AGE-RAGE axis had disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in humans. Copyright © 2010 American Physiological Society.

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