Activation of the Renal PI3K/Akt/mTOR Signaling Pathway in a DOCA-Salt Model of Hypertension

다국어 초록 (Multilingual Abstract)

The present study investigated the changes that occurred in the mammalian target of rapamycin (mTOR) signaling pathway in the kidney as a result of deoxycorticosterone acetate (DOCA)-salt hypertension. Rats were implanted with DOCA strips (200mg/kg) 1 week after unilateral nephrectomy and were then supplied with 0.9% saline to drink. Four weeks after DOCA implantation, systolic blood pressure (SBP) was measured by use of the tail-cuff method. The expression levels of phosphorylated phosphatidylinositol-3-kinase (PI3K), Akt, and mTOR, as well as the protein expression levels of ED-1 and cyclooxygenase-2 (COX-2), transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (SMA), caspase-3, Bax, and Bcl-2, were then examined in the kidney by semiquantitative immunoblotting. DOCA-salt hypertensive rats were found to have significantly increased SBP as well as an increased kidney weight-to-body weight ratio. Moreover, the phosphorylation of PI3K, Akt, and mTOR was increased in the kidney of DOCA-salt hypertensive rats compared with the control, as was the protein expression of ED-1, COX-2, TGF-β1, and α-SMA. The expression levels of caspase-3 and Bax were increased significantly, whereas Bcl-2 expression was decreased. In conclusion,the phosphorylation of PI3K/Akt/mTOR was increased in the kidney of DOCA-salt hypertensive rats.

참고문헌 (Reference)

1 Hay N, "Upstream and downstream of mTOR" 18 : 1926-1945, 2004

2 Lieberthal W, "The role of the mammalian target of rapamycin(mTOR) in renal disease" 20 : 2493-2502, 2009

3 Bae EH, "Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats" 33 : 255-262, 2010

4 Chen JK, "Role of mammalian target of rapamycin signaling in compensatory renal hypertrophy" 16 : 1384-1391, 2005

5 Bae EH, "Renoprotective effect of rosuvastatin in DOCA-salt hypertensive rats" 25 : 1051-1059, 2010

6 Sataranatarajan K, "Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin" 171 : 1733-1742, 2007

7 Wu MJ, "Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis" 69 : 2029-2036, 2006

8 Liu Y., "Rapamycin and chronic kidney disease: beyond the inhibition of inflammation" 69 : 1925-1927, 2006

9 Park JW, "Paricalcitol attenuates cyclosporine-induced kidney injury in rats" 77 : 1076-1085, 2010

10 Iwazu Y, "Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats" 29 : 2440-2453, 2011

11 Lloberas N, "Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats" 17 : 1395-1404, 2006

12 Diekmann F, "Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass" 18 : 2653-2660, 2007

13 Gavras H, "Malignant hypertension resulting from deoxycorticosterone acetate and salt excess: role of renin and sodium in vascular changes" 36 : 300-309, 1975

14 Iglarz M, "Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system" 17 : 597-603, 2004

15 Hostetter TH, "Hyperfiltration and glomerulosclerosis" 23 : 194-199, 2003

16 Mariappan MM, "High glucose, high insulin, and their combination rapidly induce laminin-beta1 synthesis by regulation of mRNA translation in renal epithelial cells" 56 : 476-485, 2007

17 Katso R, "Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer" 17 : 615-675, 2001

18 Lijnen PJ, "Association between transforming growth factor-beta and hypertension" 16 : 604-611, 2003

19 Miyajima A, "Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction" 58 : 2301-2313, 2000

20 Bae EH, "Altered regulation of renal sodium transporters and natriuretic peptide system in DOCA-salt hypertensive rats" 157 : 76-83, 2009

21 Huang S, "Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation" 296 : 1323-1333, 2009

22 Sun Y, "Aldosterone-induced inflammation in the rat heart : role of oxidative stress" 161 : 1773-1781, 2002