Influence of irbesartan on expression of ilk and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction

ABSTRACT AIM: Irbesartan, a new antagonist of the type 1 angiotensin II receptor, has been proven to be renal protective in both diabetic and non-diabetic nephropathy, but its exact

mechanism is still uncertain. Here we investigated the influence of irbesartan on the expression of the integrin-linked kinase (ILK) and its relationship with epithelial-mesenchymal

transition (EMT) in mice with unilateral ureteral obstruction (UUO). METHODS: The mice were randomly divided into 3 groups: sham operation (C, _n_=20), UUO (_n_=40), and UUO with irbesartan

treatment (UUO+irbesartan, _n_=40). Irbesartan was given at a dose of 50 mg/kg body weight per day by gavage. The experimental animals in the control group received the same volume of

vehicle (0.9% saline solution). The animals were sacrificed at d 1, 3, 7, and 14, respectively, after the surgery. RESULTS: The expression of the ILK at mRNA and protein levels were

significantly increased in the UUO group 1 d after the surgery, which was significantly decreased by treatment with irbesartan (_P_ < 0.01, respectively). The expression of α-smooth

muscle actin (α-SMA) was significantly increased, while E-cadherin was decreased in mice with UUO at d 3 after the surgery. Treatment with irbesartan significantly abrogated such effects

(_P_< 0.01). The immunohistochemistry analysis indicated that the protein expression of the ILK was positively correlated with α-SMA, but negatively with E-cadherin. CONCLUSION: These

results suggested that irbesartan attenuated renal tubulointerstitial fibrosis in UUO mice, which may be related to the inhibition of ILK expression, subsequently preventing the tubular EMT.

SIMILAR CONTENT BEING VIEWED BY OTHERS LEUCINE-RICH ALPHA-2-GLYCOPROTEIN 1 DEFICIENCY SUPPRESSES ISCHEMIA–REPERFUSION INJURY-INDUCED RENAL FIBROSIS Article Open access 08 January 2025

CYANIDIN-3-GLUCOSIDE UPREGULATED NDRG2 THROUGH THE PI3K/AKT PATHWAY TO ALLEVIATE EMT AND ECM IN RENAL FIBROSIS Article Open access 28 March 2025 PROXIMAL TUBULAR RAGE MEDIATED THE RENAL

FIBROSIS IN UUO MODEL MICE VIA UPREGULATION OF AUTOPHAGY Article Open access 23 April 2022 ARTICLE PDF REFERENCES * Faulkner JL, Szcykalski LM, Springer F, Barnes JL . Origin of interstitial

fibroblasts in an accelerated model of angiotensin II- induced renal fibrosis. _Am J Pathol_ 2005; 167: 1193–205. Article  CAS  Google Scholar  * Yang J, Shultz RW, Mars WM, Wegner RE, Li

Y, Dai C, _et al_. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. _J Clin Invest_ 2002; 110: 1525–38. Article 

CAS  Google Scholar  * Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, _et al_. Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation

_in vitro_. _Kidney Int_ 1999; 56: 1455–67. Article  CAS  Google Scholar  * Li Y, Yang J, Dai C, Wu C, Liu Y . Role of integrin-linked kinase in mediating tubular epithelial to mesenchymal

transition and renal interstitial fibrogenesis. _J Clin Invest_ 2003; 112: 503–16. Article  CAS  Google Scholar  * Wu CY . The PINCH-ILK-parvin complexes: assembly, functions and regulation.

_Biochim Biophys Acta_ 2004; 1692: 55–62. Article  CAS  Google Scholar  * Ruiz-Torres MP, Lopez-Ongil S, Griera M, Diez-Marques ML, Rodriguez-Puyol M, Rodriguez-Puyol D . The accumulation

of extracellular matrix in the kidney: consequences on cellular function. _J Nephrol_ 2005; 18: 334–40. CAS  PubMed  Google Scholar  * Kretzler M, Teixeira VP, Unschuld PG, Cohen CD, Wanke

R, Edenhofer I, _et al_. Integrin-linked kinase as a candidate downstream effector in proteinuria. _FASEB J_ 2001; 15: 1843–5. Article  CAS  Google Scholar  * Guo L, Sanders PW, Woods A, Wu

C . The distribution and regulation of integrin-linked kinase in normal and diabetic kidneys. _Am J Pathol_ 2001; 159: 1735–42. Article  CAS  Google Scholar  * Ruiz-Ortega M, Ruperez M,

Esteban V, Egido J . Molecular mechanisms of angiotensin II-induced vascular injury. _Curr Hypertens Rep_ 2003; 5: 73–9. Article  Google Scholar  * Misseri R, Rink RC, Meldrum DR, Meldrum KK

. Inflammatory mediators and growth factors in obstructive renal injury. _J Surg Res_ 2004; 119: 149–59. Article  CAS  Google Scholar  * Ruiz-Ortega M, Ruperez M, Esteban V, Rodriguez-Vita

J, Sanchez-Lopez E, Carvajal G, _et al_. Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney disease. _Nephrol Dial Transplant_ 2006; 21: 16–20. Article  CAS 

Google Scholar  * Remuzzi G, Perico N, Macia M, Ruggenenti P . The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. _Kidney Int_ 2005; 68 ( Suppl

99): S57–65. Article  Google Scholar  * Klahr S, Morrissey J . Obstructive nephropathy and renal fibrosis. _Am J Physiol Renal Physiol_ 2002; 283: F861–75. Article  Google Scholar  * Aros C,

Remuzzi G . The renin-angiotensin system in progression, remission and regression of chronic nephropathies. _J Hyperten_ 2002; 20 ( Suppl 3): S45–43. CAS  Google Scholar  * Zeisberg M,

Kaluri R . The role of epithelial-to-mesenchymal transition in renal fibrosis. _J Mol Med_ 2004; 82: 175–81. Article  Google Scholar  * Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson

EG . Evidence that fibroblasts derive from epithelium during tissue fibrosis. _J Clin Invest_ 2002; 110: 341–50. Article  CAS  Google Scholar  * Yang J, Liu Y . Dissection of key events in

tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. _Am J Pathol_ 2001; 159: 1465–75. Article  CAS  Google Scholar  * Lan HY . Tubular

epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. _Curr Opin Nephrol Hypertens_ 2003; 12: 25–9. Article  CAS  Google Scholar  * Nawshad A, Lagamba D, Polad

A, Hay ED . Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. _Cells Tissues Organs_ 2005; 179:

11–23. Article  CAS  Google Scholar  * Liu YH . Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. _J Am

Soc Nephrol_ 2004; 15: 1–12. Article  CAS  Google Scholar  * Bernardo RI, Richard JJ, Jaime HA . Tubulointerstitial damage and progression of renal failure. _Kidney Int_ 2005; 68 ( Suppl

99): S82–6. Google Scholar  * Ha H, Lee HB . Reactive oxygen species and matrix remodeling in diabetic kidney. _J Am Soc Nephrol_ 2003; 14: S246–9. Article  CAS  Google Scholar  * Yang J,

Dai C, Liu Y . Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. _J Am Soc Nephrol_ 2002; 13: 2464–77. Article

  CAS  Google Scholar  * Chen L, Liu BC, Zhang XL, Zhang JD, Liu H, Li MX . Influence of connective tissue growth factor antisense oligonucleotide on angiotensin II-induced epithelial

mesenchymal transition in HK2 cells. _Acta Pharmacol Sin_ 2006; 27: 1029–36. Article  CAS  Google Scholar  * Green K, Watt F . Cell-to-cell contact and extracellular matrix. _Curr Opin Cell

Biol_ 2004; 16: 465–9. Article  CAS  Google Scholar  * Oloumi A, McPhee T, Dedhar S . Regulation of E-cadherin expression and β-catenin/Tcf transcriptional activity by the integrin-linked

kinase. _Biochim Biophys Acta_ 2004; 1691: 1–15. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Institute of Nephrology, Zhong Da Hospital,

Southeast University, Nanjing, 210009, China Bi-cheng Liu, Hui-ling Xia, Ji-ning Wu, Xiao-liang Zhang, Dian-ge Liu & Yu-xiang Gong Authors * Bi-cheng Liu View author publications You can

also search for this author inPubMed Google Scholar * Hui-ling Xia View author publications You can also search for this author inPubMed Google Scholar * Ji-ning Wu View author publications

You can also search for this author inPubMed Google Scholar * Xiao-liang Zhang View author publications You can also search for this author inPubMed Google Scholar * Dian-ge Liu View author

publications You can also search for this author inPubMed Google Scholar * Yu-xiang Gong View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to Bi-cheng Liu. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, Bc., Xia, Hl., Wu, Jn. _et al._ Influence of irbesartan on

expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction. _Acta Pharmacol Sin_ 28, 1810–1818 (2007).

https://doi.org/10.1111/j.1745-7254.2007.00649.x Download citation * Received: 22 February 2007 * Accepted: 16 May 2007 * Issue Date: 01 November 2007 * DOI:

https://doi.org/10.1111/j.1745-7254.2007.00649.x SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * irbesartan * integrin-linked kinase *

epithelial-mesenchymal transition * tubulointerstitial fibrosis