Background: High glucose and angiotensin II (Ang II) can activate protein kinase C (PKC) in diabetes mellitus. However, it is not clear which isoform of PKC is activated by glucose or Ang II. Our study focused on the effects of angiotensin blockade, using the angiotensin-converting enzyme inhibitor fosinopril, the Ang II receptor blocker irbesartan and their combination, on the expression and translocation of PKC isoforms α and βII in the renal cortex and medulla in diabetes. Methods: Hyperglycemia was induced with streptozotocin and diabetic rats were randomized to 4 groups: diabetic control, irbesartan group (40 mg/kg daily), fosinopril group (40 mg/kg daily) and combination group (irbesartan plus fosinopril, 20 mg/kg daily, respectively); age-matched normal rats served as normal control. After 4 weeks, expression and translocation of PKC-α and -βII in the renal cortex and medulla were assessed by immunohistochemistry and Western immunoblotting. Results: The expression of PKC-α in the membrane and cytosol fractions from the renal cortex was significantly higher in diabetic rats (276.83 ± 32.44% in membrane, 149.04 ± 23.42% in cytosol) than that in normal ones. The expression of PKC-βII in the renal cortex of diabetic rats decreased significantly in the membrane (50.00 ± 11.68%, p < 0.05) and remained unchanged in the cytosol (94.51 ± 11.69%, p > 0.05) compared with normal controls. Treatment with irbesartan, fosinopril and their combination partially corrected the abnormalities mentioned above. For the expression of PKC-α and -βII in the medulla, no difference was detected among the 5 groups. Conclusion: The renin-angiotensin system was implicated in the pathogenesis of diabetic nephropathy by regulating the activation of PKC isoforms.

Excerpts from United States Renal Data System 1999 Annual Data Report. Am J Kidney Dis 1999;34(suppl 1):S1&ndash;S176.
King GL, Kunisaki M, Nishino Y, Inoguchi T, Shiba T, Xia P: Biochemical and molecular mechanisms in the development of diabetic vascular complications. Diabetes 1996;45(suppl 3):S105&ndash;S108.
Wolf G, Ziyadeh PN: The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 1997;29:153&ndash;163.
Koide H, Nakamura T, Ebihara I, Fukui M: Endothelins in diabetic kidneys. Kidney Int 1995;48(suppl 51):S45&ndash;S49.
Sharma K, Ziyadeh FN: Hyperglycemia and diabetic kidney disease: the case for transforming growth factor &beta; as a key mediator. Diabetes 1995;44:1139&ndash;1146.
Soulis-Liparota T, Cooper M, Papazoglou D, Clarke B, Jerume G: Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozotocin-induced diabetic rat. Diabetes 1991;40:1328&ndash;1334.
Craven PA, Studer PK, Negrete H, De Rubertis FR: Protein kinase C in diabetic nephropathy. J Diabetes Compl 1995;9:241&ndash;245.
Inaba T, Ishibashi S, Gotoda T, Kawamura M, Morio N, Nojima Y, Kawakami M, Yazaki Y, Yamada N: Enhanced expression of platelet-derived growth factor &beta; receptor by high glucose: involvement of platelet-derived growth factor in diabetic angiopathy. Diabetes 1996;45:507&ndash;512.
DeRubertis FR, Craven PA: Activation of protein kinase C in glomerular cells in diabetes: mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 1994;43:1&ndash;8.
Craven PA, DeRubertis FR: Protein kinase C is activated in glomeruli from streptozotocin diabetic rats: possible mediation by glucose. J Clin Invest 1989;83:1667&ndash;1675.
Ishii H, Koya D, King GL: Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 1998;76:21&ndash;31.
Haller H, Baur E, Quass P, Behrend M, Lindschau C, Disler A, Luft FC: High glucose concentrations and protein kinase C isoforms in vascular smooth muscle cells. Kidney Int 1995;47:1057&ndash;1067.
Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL: Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 1994;43:1122&ndash;1129.
Barnett RL, Ruffini L, Ramsammy L, Pasmantier R, Friedlaender MM, Nord EP: Angiotensin-mediated phosphatidylcholine hydrolysis and protein kinase C activation in mesangial cells. Am J Physiol 1993;265:C1100&ndash;C1108.
Musial A, Mandal A, Coroneos E, Kester M: Interleukin-1 and endothelin stimulate distinct species of diglycerides that differentially regulate protein kinase C in mesangial cells. J Biol Chem 1995;270:21632&ndash;21638.
Studer RK, Negret H, Craven PA, DeRubertis FR: Protein kinase C signals thromboxane induced increases in fibronectin synthesis and TGF-&beta; bioactivity in mesangial cells. Kidney Int 1995;48:422&ndash;430.
Ganz MB, Saksa B, Saxena R, Hawkins K, Sedor JR: PDGF and IL-1 induce and activate specific protein kinase C isoforms in mesangial cells. Am J Physiol 1996;271:F108&ndash;F113.
Karim Z, Defontaine N, Paillard M, Poggioli J: Protein kinase C isoforms in rat kidney proximal tubule: acute effect of angiotensin II. Am J Physiol 1995;269:C134&ndash;C140.
Siragy HM: Angiotensin II receptor blockers: review of the binding characteristics. Am J Cardiol 1999;84:3S&ndash;7S.
Berman MA, Walsh MF, Sowers JR: Angiotensin-II biochemistry and physiology: update on angiotensin-II receptor blockers. Cardiovasc Drug Rev 1997;15:75&ndash;100.
Haller H, Lindschau C, Luft FC: Role of protein kinase C in intracellular signaling. Ann NY Acad Sci 1994;733:313&ndash;324.
Hofmann J: The potential for isoenzymes-selective modulation of protein kinase C. FASEB J 1997;11:649&ndash;669.
Berman MA, Walsh MF, Sowers JR: Angiotensin-II biochemistry and physiology: update on angiotensin-II receptor blockers. Cardiovasc Drug Rev 1997;15:75&ndash;100.
Babazono T, Kapor-Drezgic J, Diugosz JA, Whiteside C: Altered expression and subcellular localization of diacylglycerol-sensitive protein kinase C isoforms in diabetic rat glomerular cells. Diabetes 1998;47:668&ndash;676.
Kang N, Alexander G, Park JK, Maasch C, Buchwalow I, Luft F, Haller H: Differential expression of protein kinase C isoforms in streptozotocin-induced diabetic rats. Kidney Int 1999;56:1737&ndash;1750.
Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC&beta; inhibitor. Science 1996;272:728&ndash;731.
Kikkawa R, Haneda M, Uzu T, Koya D, Sugimoto T, Shigeta Y: Translocation of protein kinase C&alpha; and &xi; in rat glomerular mesangial cells cultured under high glucose conditions. Diabetologia 1994;37:838&ndash;841.
Thallas-Bonke V, Lindschau C, Rizkalla B, Bach LA, Boner G, Meier M, Haller H, Cooper ME, Forbes JM: Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-&alpha;-dependent pathway. Diabetes 2004;53:2921&ndash;2930.
Haller H, Park JK, Dragun D, Lippoldt A, Luft F: Leukocyte infiltration and ICAM-1 expression in two-kidney one-clip hypertension. Nephrol Dial Transplant 1997;12:899&ndash;903.
Ayo SH, Radpik R, Caroni JA, et al: High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cell cultures. Am J Physiol 1991;261:F571&ndash;F577.
Anderson S, Jung FF, Ingelfinger JR: Renin-angiotensin system in diabetic rats: functional, immunohistochemical, and molecular biological correlations. Am J Physiol 1993;265:F477&ndash;F486.
Hsueh WA, Anderson PW: Systemic hypertension and the renin-angiotensin system in diabetic vascular complications. Am J Cardiol 1993;72:14H&ndash;21H.
Kikkawa R, Kitamura E, Fujiwara Y, Haneda M, Shigeta Y: Biphasic alteration of renin-angiotensin-aldosterone system in streptozotocin-diabetic rats. Renal Physiol 1986;9:187&ndash;192.
Seikaly MG, Arant BSJ, Seney FDJ: Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest 1990;86:1352&ndash;1357.
Cheng HF, Becker BN, Burns KD, Harris RC: Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. J Clin Invest 1995;95:2012&ndash;2019.
Perico N, Amuchastegui SC, Colosio V, Sonzogni G, Bertani Y, Remuzzi G: Evidence that an angiotensin-converting enzyme inhibitor has a different effect in glomerular injury according to the different phase of the disease at which the treatment is started. J Am Soc Nephrol 1994;5:1139&ndash;1146.
Chiu R, Boyle WJ, Meek J, Smeal T, Hunter T, Karin M: The c-fos protein interacts with c-jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 1988;54:541&ndash;552.
Liu FY, Cogen MG: Role of protein kinase C in proximal bicarbonate absorption and angiotensin signaling. Am J Physiol 1990;258:F927&ndash;F933.
Meier M, Park JK, Boehne M, Leitges M, Haller H, Menne J: Knockout of protein kinase C alpha protects against the development of albuminuria but not renal hypertrophy. Diabetes 2003;52:A50.
Menne J, Park JK, Boehne M, Elger M, Lindschau C, Kirsch T, Meier M, Gueler F, Fiebeler A, Bahlmann FH, Leitges M, Haller H: Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice. Diabetes 2004;53:2101&ndash;2109.
Campbell DJ, Kladis A, Valentijn AJ: Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol 1995;26:233&ndash;240.
Arima S, Endo Y, Yaoita H, Omata K, Ogawa S, Tsunoda K, Abe M, Takeuchi K, Abe K, Ito S: Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole. J Clin Invest 1997;100:2816&ndash;2823.
Kon V, Fogo A, Ichikawa I: Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition. Kidney Int 1993;44:545&ndash;550.
Allen TJ, Cao Z, Youssef S, Hulthen UL, Cooper ME: Role of angiotensin II and bradykinin in experimental diabetic nephropathy: functional and structural studies. Diabetes 1997;46:1612&ndash;1618.
Brown NJ, Agirbasli M, Vaughan DE: Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension 1999;34:285&ndash;290.
Peters H, Border WA, Noble NA: Targeting TGF-beta overexpression: maximizing the antifibrotic action of angiotensin II blockade. Kidney Int 1998;54:1570&ndash;1580.
Campbell DJ, Kladis A, Duncan AM: Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides. Hypertension 1994;23:439&ndash;449.
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