Prednisone inhibits the focal adhesion kinase/receptor activator of NF-κB ligand/mitogen-activated protein kinase signaling pathway in rats with adriamycin-induced nephropathy

Ye,Minyuan; Zheng,Jing; Chen,Xiaoying; Chen,Xuelan; Wu,Xinhong; Lin,Xiuqin; Liu,Yafang

doi:10.3892/mmr.2015.4370

Prednisone inhibits the focal adhesion kinase/receptor activator of NF-κB ligand/mitogen-activated protein kinase signaling pathway in rats with adriamycin-induced nephropathy

Authors:
- Minyuan Ye
- Jing Zheng
- Xiaoying Chen
- Xuelan Chen
- Xinhong Wu
- Xiuqin Lin
- Yafang Liu
View Affiliations

Affiliations: Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Department of Nephropathy, The People's Hospital of Fujian Province, Fuzhou, Fujian 350004, P.R. China
Published online on: September 25, 2015 https://doi.org/10.3892/mmr.2015.4370
Pages: 7471-7478

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the mechanisms underlying the effects of prednisone on adriamycin-induced nephritic rat kidney damage via the focal adhesion kinase (FAK)/receptor activator of nuclear factor-κB ligand (RANKL)/mitogen‑activated protein kinase (MAPK) signaling pathway. An adriamycin‑induced nephritic rat model was established to investigate these mechanisms. A total of 30 healthy male Sprague‑Dawley rats were randomly assigned to the normal, model or prednisone group. Samples of urine were collected over the course of 24 h at days 7, 14, and 28, and renal cortex tissue samples were harvested at days 14, and 28 following nephritic rat model establishment. The total urinary protein content was measured by biuret colorimetry. Pathological changes in the kidney tissue samples were observed using an electron microscope. The mRNA expressions levels of FAK, RANKL, p38, extracellular signal‑regulated kinase (ERK), c‑Jun N‑terminal kinase (JNK), and nephrin were then quantified by reverse transcription‑quantitative polymerase chain reaction. In addition, the protein expressions levels of FAK, RANKL, p38, ERK, JNK, phosphorylated (p)‑FAK, p‑ERK, and p‑JNK were quantified by western blotting. As compared with the normal group, the protein expression levels of FAK, RANKL, p-FAK, p38 and p-ERK in the model group were increased. In the prednisone group, the protein expression levels of p-ERK decreased, as compared with the normal group. In the prednisone group, the urinary protein levels, the protein expression levels of FAK, RANKL, p38, p-FAK, p-p38 and the mRNA expression levels of FAK, p38, RANKL, ERK, JNK decreased, as compared with the model group. In the prednisone group, the mRNA and protein expression levels of nephrin and the serum expression levels of RANKL increased, the serum expression levels of osteoprotegerin (OPG) were decreased, as compared with the model group. No significant changes in the protein expression levels of JNK were observed among the groups. These results suggested that prednisone is able to protect podocytes from apoptosis, and reduce urinary protein levels by inhibiting the FAK/RANKL/MAPK signaling pathway in kidney tissue samples. Serum prednisone may induce osteoporosis via the OPG/RANK/RANKL signaling pathway.

View Figures

View References

1	Ma H, Togawa A, Soda K, Zhang J, Lee S, Ma M, Yu Z, Ardito T, Czyzyk J, Diggs L, et al: Inhibition of podocyte FAK protects against proteinuria and foot process effacement. J Am Soc Nephrol. 21:1145–1156. 2010. View Article : Google Scholar : PubMed/NCBI
2	Kanasaki K, Kanda Y, Palmsten K, Tanjore H, Lee SB, Lebleu VS, Gattone VH Jr and Kalluri R: Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus. Dev Biol. 313:584–593. 2008. View Article : Google Scholar
3	Koshikawa M, Mukoyama M, Mori K, Suganami T, Sawai K, Yoshioka T, Nagae T, Yokoi H, Kawachi H, Shimizu F, et al: Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome. J Am Soc Nephrol. 16:2690–2701. 2005. View Article : Google Scholar : PubMed/NCBI
4	Shuyu L and Zhigang W: The progress on focal adhesion kinase (FAK) and its single pathways. Biotechnol Inf. 12:6–10. 2009.In Chinese.
5	Kaminska B: MAPK signalling pathways as molecular targets for anti-inflammatory therapy - from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta. 1754:253–262. 2005. View Article : Google Scholar : PubMed/NCBI
6	Rogers A and Eastell R: Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: Clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab. 90:6323–6331. 2005. View Article : Google Scholar : PubMed/NCBI
7	Liu S, Shi W, Xiao H, Liang X, Deng C, Ye Z, Mei P, Wang S, Liu X, Shan Z, et al: Receptor activator of NF-kappaB and podocytes: Towards a function of a novel receptor-ligand pair in the survival response of podocyte injury. PLoS One. 7:e413312012. View Article : Google Scholar : PubMed/NCBI
8	Papachroni KK, Karatzas DN, Papavassiliou KA, Basdra EK and Papavassiliou AG: Mechanotransduction in osteoblast regulation and bone disease. Trends Mol Med. 15:208–216. 2009. View Article : Google Scholar : PubMed/NCBI
9	Zhang DW, Huang XZ, Wu JH, Fan YP and Shi H: Effects of intercellular adhesion molecule-1 on renal damage in spontaneously hypertensive rats. Ren Fail. 34:915–920. 2012. View Article : Google Scholar : PubMed/NCBI
10	Sun W, He Y, Yu J, Lin Y, Wang Y, Gao X, Wang Y, Zhao Z and Liu X: Effect of yiqiyangyin recipe on heparanase and nephrin in rats with adriamycin-induced nephropathy. J Tradit Chin Med. 33:334–342. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zhang Y, Yoshida Y, Nameta M, Xu B, Taguchi I, Ikeda T, Ceccarelli DF, Song HK, Poy F, Schaller MD and Eck MJ: Crystal structure of the FERM domain of focal adhesion kinase. J Biol Chem. 281:252–259. 2006. View Article : Google Scholar
12	Fujinaka H, Magdeldin S, Tsukaguchi H, Harita Y, et al: Glomerular proteins related to slit diaphragm and matrix adhesion in the foot processes are highly tyrosine phosphory lated in the normal rat kidney. Nephrol Dial Transplant. 25:1785–1795. 2010. View Article : Google Scholar
13	Yang L, Liang M, Zhou Q, Xie D, Lou A, Zhang X and Hou F: Advanced oxidation protein products decrease expression of nephrin and podocin in podocytes via ROS-dependent activation of p38 MAPK. Sci China Life Sci. 53:68–77. 2010. View Article : Google Scholar : PubMed/NCBI
14	El-Aouni C, Herbach N, Blattner SM, Henger A, Rastaldi MP, Jarad G, Miner JH, Moeller MJ, St-Arnaud R, Dedhar S, et al: Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. J Am Soc Nephrol. 17:1334–1344. 2006. View Article : Google Scholar : PubMed/NCBI
15	Boyce BF, Yao Z and Xing L: Functions of nuclear factor kappaB in bone. Ann N Y Acad Sci. 1192:367–375. 2010. View Article : Google Scholar : PubMed/NCBI
16	Romas E, Sims NA, Hards DK, Lindsay M, Quinn JW, Ryan PF, Dunstan CR, Martin TJ and Gillespie MT: Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. The American Journal of Pathology. 161:1419–1427. 2002. View Article : Google Scholar : PubMed/NCBI
17	Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, et al: The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 103:41–50. 2000. View Article : Google Scholar : PubMed/NCBI
18	Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D and Dougall WC: RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 468:103–107. 2010. View Article : Google Scholar : PubMed/NCBI
19	Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y, Schneider P and Brisken C: Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci USA. 107:2989–2994. 2010. View Article : Google Scholar : PubMed/NCBI
20	Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, Quinn JM, Niforas P, Ng KW, Martin TJ and Gillespie MT: Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone. 25:525–534. 1999. View Article : Google Scholar : PubMed/NCBI
21	Rauner M, Sipos W, Thiele S and Pietschmann P: Advances in osteoimmunology: Pathophysiologic concepts and treatment opportunities. Int Arch Immunol. 160:114–125. 2013. View Article : Google Scholar
22	Reichardt H, Tuckermann J, Göttlicher M, Vujic M, Weih F, Angel P, Herrlich P and Schütz G: Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 20:7168–7173. 2001. View Article : Google Scholar : PubMed/NCBI
23	Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, et al: Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12:1260–1268. 1998. View Article : Google Scholar : PubMed/NCBI
24	Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M and Dobnig H: Vascular calcification and osteoporosis - from clinical observation towards molecular understanding. Osteoporos Int. 18:251–259. 2007. View Article : Google Scholar