Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice.
Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-alpha is activated in the kidneys of hyperglycemic animals. We now used PKC-alpha(-/-) mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy. We observed that renal and glomerular hypertrophy was similar in diabetic wild-type and PKC-alpha(-/-) mice. However, the development of albuminuria was almost absent in the diabetic PKC-alpha(-/-) mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-alpha(-/-) mice, compared with controls. We then asked whether transforming growth factor-beta1 (TGF-beta1) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-alpha-mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-alpha(-/-) mice, whereas expression of TGF-beta1 was not affected by the lack of PKC-alpha. Our findings indicate that two important features of diabetic nephropathy-glomerular hypertrophy and albuminuria-are differentially regulated. The glucose-induced albuminuria seems to be mediated by PKC-alpha via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-alpha is a possible therapeutic target for the prevention of diabetic albuminuria.
Phenos, Hannover, Germany.
Jan
J
Menne
Joon-Keun
JK
Park
Martin
M
Boehne
Marlies
M
Elger
Carsten
C
Lindschau
Torsten
T
Kirsch
Matthias
M
Meier
Faikah
F
Gueler
Annette
A
Fiebeler
Ferdinand H
FH
Bahlmann
Michael
M
Leitges
Hermann
H
Haller
D000419:Albuminuria / Q000652:urine; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000652:urine; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology / Q000652:urine; D006943:Hyperglycemia / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000033:anatomy & histology / Q000473:pathology / Q000648:ultrastructure; D007678:Kidney Glomerulus / Q000033:anatomy & histology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009929:Organ Size; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics*; D051571:Protein Kinase C-alpha; D011509:Proteoglycans / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D001786:Blood Glucose; D017931:DNA Primers; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha