Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension.
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) beta. The present study thus sought to determine the in vivo effect of PKC beta 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 beta inhibitor, LY333531, admixed in diet (10 mg x kg(-1) x d(-1)) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-beta (TGF-beta). Western blot analysis demonstrated increased PKC beta in diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC beta with LY333531 led to a reduction in albuminuria, structural injury, and TGF-beta expression, despite continued hypertension and hyperglycemia.
Kelly
Darren J
DJ
Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia. dkelly@medstv.unimelb.edu.au
Zhang
Yuan
Y
Hepper
Claire
C
Gow
Renae M
RM
Jaworski
Kassie
K
Kemp
Bruce E
BE
Wilkinson-Berka
Jennifer L
JL
Gilbert
Richard E
RE
D000419:Albuminuria; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D003925:Diabetic Angiopathies / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006973:Hypertension / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D007668:Kidney / Q000033:anatomy & histology / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008301:Maleimides / Q000627:therapeutic use*; D009929:Organ Size; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051381:Rats; D011922:Rats, Mutant Strains; D012016:Reference Values
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta