Chonnam Med J.  2012 Dec;48(3):150-154. 10.4068/cmj.2012.48.3.150.

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

• Ma SK
• Choi JS
• Joo SY
• Kim HY
• Kim CS
• Bae EH
• Lee JU
• Kim SW

• KMID: 2048803
• DOI: http://doi.org/10.4068/cmj.2012.48.3.150

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 (200 mg/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-beta1 (TGF-beta1), alpha-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-beta1, and alpha-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.

Keyword

Deoxycorticosterone; Hypertension; Kidney

MeSH Terms

Actins
Animals
Blood Pressure
Caspase 3
Cyclooxygenase 2
Desoxycorticosterone
Hypertension
Immunoblotting
Kidney
Muscles
Nephrectomy
Phosphorylation
Rats
Sirolimus
Transforming Growth Factor beta1
Actins
Caspase 3
Cyclooxygenase 2
Desoxycorticosterone
Sirolimus
Transforming Growth Factor beta1

Figure

• 

  FIG. 1 Expression of phosphorylated phosphatidylinositol-3-kinase (p-PI3K), phosphorylated Akt (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR) in the kidney. DOCA, deoxycorticosterone acetate. *p<0.05 compared with the control.

• 

  FIG. 2 Expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA) in the kidney. DOCA: deoxycorticosterone acetate. *p<0.05 compared with the control.

• 

  FIG. 3 Expression of caspase-3, Bax, and Bcl-2 in the kidney. DOCA: deoxycorticosterone acetate. *p<0.05 compared with the control.

Reference

1. Gavras H, Brunner HR, Laragh JH, Vaughan ED Jr, Koss M, Cote LJ, et al. Malignant hypertension resulting from deoxycorticosterone acetate and salt excess: role of renin and sodium in vascular changes. Circ Res. 1975. 36:300–309.

2. Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens. 2004. 17:597–603.

3. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart : role of oxidative stress. Am J Pathol. 2002. 161:1773–1781.

4. Lijnen PJ, Petrov VV, Fagard RH. Association between transforming growth factor-beta and hypertension. Am J Hypertens. 2003. 16:604–611.

5. Liu Y. Rapamycin and chronic kidney disease: beyond the inhibition of inflammation. Kidney Int. 2006. 69:1925–1927.

6. Lieberthal W, Levine JS. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol. 2009. 20:2493–2502.

7. Huang S, Zhang A, Ding G, Chen R. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am J Physiol Renal Physiol. 2009. 296:F1323–F1333.

8. Bae EH, Kim IJ, Ma SK, Kim SW. Altered regulation of renal sodium transporters and natriuretic peptide system in DOCA-salt hypertensive rats. Regul Pept. 2009. 157:76–83.

9. Bae EH, Kim IJ, Park JW, Ma SK, Lee JU, Kim SW. Renoprotective effect of rosuvastatin in DOCA-salt hypertensive rats. Nephrol Dial Transplant. 2010. 25:1051–1059.

10. Bae EH, Kim IJ, Ma SK, Kim SW. Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats. Hypertens Res. 2010. 33:255–262.

11. Iwazu Y, Muto S, Hirahara I, Fujisawa G, Takeda S, Kusano E. Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats. J Hypertens. 2011. 29:2440–2453.

12. Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J, et al. Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int. 2000. 58:2301–2313.

13. Park JW, Bae EH, Kim IJ, Ma SK, Choi C, Lee J, et al. Paricalcitol attenuates cyclosporine-induced kidney injury in rats. Kidney Int. 2010. 77:1076–1085.

14. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001. 17:615–675.

15. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004. 18:1926–1945.

16. Hostetter TH. Hyperfiltration and glomerulosclerosis. Semin Nephrol. 2003. 23:194–199.

17. Chen JK, Chen J, Neilson EG, Harris RC. Role of mammalian target of rapamycin signaling in compensatory renal hypertrophy. J Am Soc Nephrol. 2005. 16:1384–1391.

18. Mariappan MM, Feliers D, Mummidi S, Choudhury GG, Kasinath BS. High glucose, high insulin, and their combination rapidly induce laminin-beta1 synthesis by regulation of mRNA translation in renal epithelial cells. Diabetes. 2007. 56:476–485.

19. Sataranatarajan K, Mariappan MM, Lee MJ, Feliers D, Choudhury GG, Barnes JL, et al. Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin. Am J Pathol. 2007. 171:1733–1742.

20. Lloberas N, Cruzado JM, Franquesa M, Herrero-Fresneda I, Torras J, Alperovich G, et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J Am Soc Nephrol. 2006. 17:1395–1404.

21. Wu MJ, Wen MC, Chiu YT, Chiou YY, Shu KH, Tang MJ. Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int. 2006. 69:2029–2036.

22. Diekmann F, Rovira J, Carreras J, Arellano EM, Bañón-Maneus E, Ramírez-Bajo MJ, et al. Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass. J Am Soc Nephrol. 2007. 18:2653–2660.