Inhibition of Protein Kinase C Prevents Rapid Desensitization of Type 1B Angiotensin II Receptor

Primary cultures of neonatal cardiac myocytes were used to determine the identity of second messengers that are involved in angiotensin II (ANG II) receptor-mediated effects on cardiac hypertrophy and the type of ANG II receptor that is involved in ANG II-induced cell growth. Treatment of myocytes with ANG II significantly increased the protein-to-DNA and the RNA-to-DNA ratios. ANG II accelerated rates of protein synthesis by 24.9%. Intracellular free calcium was transiently increased after ANG II exposure. The activity of protein kinase C in particulate fractions was transiently increased after exposure to ANG II but returned to control level. The activity of protein kinase C in the cytosol was significantly decreased at all times after exposure to ANG II. After ANG II treatment, the content of c-Fos mRNA was increased. The stimulatory effects of ANG II on these parameters were inhibited by the type 1 angiotensin II receptor (AT1) antagonist, losartan. These studies demonstrate that ANG II-induced hypertrophic growth is, at least in part, mediated through AT1 receptors.

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Internalization of the Type I Angiotensin II Receptor (AT1) Is Required for Protein Kinase C Activation But Not for Inositol Trisphosphate Release in the Angiotensin II-Stimulated Rat Adrenal Zona Glomerulosa Cell

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1994.2603 ◽

1994 ◽

Vol 204 (3) ◽

pp. 1292-1298 ◽

Cited By ~ 17

Author(s):

S. Kapas ◽

J.P. Hinson ◽

J.R. Puddefoot ◽

M.M. Ho ◽

G.P. Vinson

Keyword(s):

Protein Kinase C ◽

Angiotensin Ii ◽

Protein Kinase ◽

Inositol Trisphosphate ◽

Zona Glomerulosa ◽

Type I ◽

Angiotensin Ii Receptor ◽

Kinase C ◽

Protein Kinase C Activation

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Different effects of phorbol ester on angiotensin II- and stable GTP analogue-induced activation of polyphosphoinositide phosphodiesterase in membranes isolated from rat renal mesangial cells

Biochemical Journal ◽

10.1042/bj2480209 ◽

1987 ◽

Vol 248 (1) ◽

pp. 209-215 ◽

Cited By ~ 31

Author(s):

J Pfeilschifter ◽

C Bauer

Keyword(s):

Protein Kinase C ◽

Angiotensin Ii ◽

Protein Kinase ◽

Phorbol Ester ◽

Mesangial Cells ◽

Angiotensin Ii Receptor ◽

Kinase C ◽

Dependent Inhibition ◽

Dose Dependent Inhibition ◽

Gamma S

Pretreatment with pertussis toxin inhibits angiotensin II-induced activation of polyphosphoinositide phosphodiesterase in rat renal mesangial cells [Pfeilschifter & Bauer (1986) Biochem. J. 236, 289-294]. Furthermore, activation of protein kinase C by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and by 1-oleoyl-2-acetylglycerol (OAG) abolishes angiotensin II-induced formation of inositol trisphosphate (IP3) in mesangial cells [Pfeilschifter (1986) FEBS Lett. 203, 262-266]. Using membrane preparations of [3H]inositol-labelled mesangial cells we tried to obtain further insight as to the step at which protein kinase C might interfere with the signal transduction mechanism in mesangial cells. Angiotensin II (100 nM) stimulates IP3 formation from membrane preparations of [3H]inositol-labelled mesangial cells with a half-maximal potency of 1.1 nM. The angiotensin II-induced formation of IP3 is enhanced by GTP. This effect of angiotensin II is completely blocked by the competitive antagonist [Sar1,Ala8]angiotensin II. Guanosine 5′-[gamma-thio]triphosphate (GTP gamma S) and guanosine 5′-[beta gamma-imido]triphosphate (Gpp[NH]p), non-hydrolysable analogues of GTP, stimulate IP3 production in the absence of angiotensin II with Kd values of 0.19 microM and 2.4 microM, respectively. Angiotensin II augments the increase in IP3 formation induced by GTP gamma S. However, when mesangial cells were pretreated with TPA there was a dose-dependent inhibition of the synergistic action of angiotensin II on GTP gamma S-induced IP3 production. Comparable results are obtained with OAG, while the non-tumour-promoting phorbol ester 4 alpha-phorbol 12,13-didecanoate is without effect. These results suggest that activation of protein kinase C in mesangial cells does not impair phosphoinositide hydrolysis by stable GTP analogues but somehow seems to interfere with the stimulatory interaction of the occupied angiotensin II receptor with the transducing G-protein.

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