Protein kinase C β inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension

Darren J. Kelly, Yuan Zhang, Claire Hepper, Renae M. Gow, Kassie Jaworski, Bruce E. Kemp, Jennifer L. Wilkinson-Berka, Richard E. Gilbert

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Abstract

In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of diabetic nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) β The present study thus sought to determine the in vivo effect of PKC β inhibition in experimental diabetic nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human diabetic nephropathy when experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, diabetic rats were further randomized to receive treatment with the specific PKC β inhibitor, LY333531, admixed in diet (10 mg · kg-1 · d-1) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-β (TGF-β). Western blot analysis demonstrated increased PKC β in diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC β with LY333531 led to a reduction in albuminuria, structural injury, and TGF-β expression, despite continued hypertension and hyperglycemia.

Original languageEnglish
Pages (from-to)512-518
Number of pages7
JournalDiabetes
Volume52
Issue number2
DOIs
Publication statusPublished - 1 Feb 2003
Externally publishedYes

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