Interleukin-1 inhibits angiotensin II-stimulated protein kinase B pathway in renal mesangial cells via the inducible nitric oxide synthase.
Exposure of rat renal mesangial cells to angiotensin II and angiotensin III leads to a rapid phosphorylation and activation of the protein kinase B (PKB) pathway. The angiotensin II analogs angiotensin-(1-7), angiotensin-(1-6) and angiotensin-(3-8) were unable to activate PKB. The angiotensin II and III effects are mediated by the angiotensin type 1 receptor as documented by the inhibitory action of valsartan. Furthermore, angiotensin II-induced activation of PKB involves neither a pertussis toxin-sensitive pathway nor the small G proteins of the Rho/Rac/cdc42 family, but is completely blocked by inhibitors of the PI 3-kinase. Moreover, angiotensin II-stimulated PKB activation is inhibited by long-term pretreatment with interleukin-1 beta, an effect that is reversed by the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA). Similarly, the nitric oxide donor (Z)-1-[2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (Deta-NO) blocks the angiotensin II-induced PKB activation. The NO-mediated inhibition of PKB activation in turn is reversed by the phosphatase inhibitor calyculin A but not by ocadaic acid, implying the induction of a protein phosphatase 1 activity by NO.
Rölz
Waltraud
W
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Xin
Cuiyan
C
Ren
Shuyu
S
Pfeilschifter
Josef
J
Huwiler
Andrea
A
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000804:Angiotensin II / Q000494:pharmacology*; D000805:Angiotensin III / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation; D004768:Enterotoxins / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000804:Angiotensin II; D000805:Angiotensin III; D001427:Bacterial Toxins; D004768:Enterotoxins; D007375:Interleukin-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D010566:Virulence Factors, Bordetella; C041348:tcdA protein, Clostridium difficile; C496318:Nos2 protein, rat