Ureter, the Guardian Angel of Nephron: The Impact of Pelvicalyceal System on Apoptotic Activity in an Experimental Obstructive Uropathy Model

  • Serhat Gürocak Gazi University, School of Medicine, Department of Urology
  • Volkan Ergin Gazi University, School of Medicine, Department of Medical Biology and Genetics
  • Ahmet Cumaoğlu Gazi University, School of Medicine, Department of Medical Biochemistry
  • İyimser Üre Osmangazi University Faculty of Medicine
  • İpek Işık Gönül Gazi University, School of Medicine, Department of Pathology
  • Aysel Arıcıoğlu Gazi University, School of Medicine, Department of Medical Biochemistry
  • İbrahim Bozkırlı
  • Adnan Menevşe Gazi University, School of Medicine, Department of Medical Biology and Genetics
Keywords: Ureteral obstruction, inflammation, genetics


Objective: We aimed to assess the impact of obstructive uropathy and its revision on renal apoptotic and inflammatory activity in an experimental model in rabbits.Methods: Twenty-four rabbits were separated into four different groups. Ureteropelvic junction (UPJ) obstruction model was performed in Group 1 and 2. Ureterovesical junction (UVJ) obstruction model was performed in Group 3 and 4. Thirty days after the operations, bilateral nephrectomy was performed in Group 1 and 3. Thirty days after the initial surgery, the obstruction was revised in Group 2 and 4. Thirty days after the revision surgeries, bilateral nephrectomy was performed in Group 2 and 4. The apoptotic and inflammatory activity was measured at the protein level and nephrectomy specimens were examined histologically. Results: Caspase 3 levels were significantly higher in operated left kidneys than the levels obtained in the right counterparts. The increase in procaspase 9 and caspase 3 activities in the UVJ obstruction group was less than those of the UPJ obstruction group (p<0.05, p<0.01, respectively). After the revision of obstruction, the decrease in procaspase 9 and caspase 3 activities was more significant in Group 4 than in Group 2 (p<0.05, p<0.01, respectively). Cyclooxygenase-2 expression decreased insignificantly in Group 2 and 4 when compared to Group 1 and 3 (p>0.05, p>0.05, respectively).Conclusion: The rabbits with a UVJ obstruction had lower apoptotic indexes as compared to those with a UPJ obstruction. The apoptotic activity decreased to almost normal levels following an adequate revision of the obstruction in both groups, but this improvement was more significant in animals with a UVJ obstruction.  


Chevalier RL. Molecular and cellular pathophysiology of obstructive nephropathy. Pediatr Nephrol Berl Ger. 1999;13:612-9.

Chevalier RL. Perinatal obstructive nephropathy. Semin Perinatol. 2004;28:124-31.

Misseri R, Rink RC, Meldrum DR, Meldrum KK. Inflammatory mediators and growth factors in obstructive renal injury. J Surg Res. 2004;119:149-59.

Kluth DC, Erwig L-P, Rees AJ. Multiple facets of macrophages in renal injury. Kidney Int. 2004;66:542-57.

Gupta A, Gupta A, Nigam D, Shukla GS, Agarwal AK. Profile of reactive oxygen species generation and antioxidative mechanisms in the maturing rat kidney. J Appl Toxicol Jat. 1999;19:55-9.

Fernandez A, Kiefer J, Fosdick L, McConkey DJ. Oxygen radical production and thiol depletion are required for Ca(2+)-mediated endogenous endonuclease activation in apoptotic thymocytes. J Immunol Baltim Md 1950. 1995;155:5133-9.

Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol. 1999;144:281-92.

Manucha W, Carrizo L, Ruete C, Vallés PG. Apoptosis induction is associated with decreased NHE1 expression in neonatal unilateral ureteric obstruction. Bju Int. 2007;100:191-8.

Nguyen HT, Bride SH, Badawy AB, Adam RM, Lin J, Orsola A, et al. Heparin-binding EGF-like growth factor is up-regulated in the obstructed kidney in a cell- and region-specific manner and acts to inhibit apoptosis. Am J Pathol. 2000;156:889-98.

Shokeir AA. Partial ureteral obstruction: a new variable and reversible canine experimental model. urology. 1995;45:953-7.

Sheerin NS, Sacks SH. Chronic interstitial damage in proteinuria. Does complement mediate tubulointerstitial injury? Kidney Blood Press Res. 1999;22:47-52.

Chevalier RL. Obstructive nephropathy: towards biomarker discovery and gene therapy. Nat Clin Pract Nephrol. 2006;2:157-68.

Schreiner GF, Harris KP, Purkerson ML, Klahr S. Immunological aspects of acute ureteral obstruction: immune cell infiltrate in the kidney. Kidney Int. 1988;34:487-93.

Sharma AK, Mauer SM, Kim Y, Michael AF. Interstitial fibrosis in obstructive nephropathy. Kidney Int.1993;44:774-88.

Vaughan ED Jr, Marion D, Poppas DP, Felsen D. Pathophysiology of unilateral ureteral obstruction: studies from Charlottesville to New York. J Urol. 2004;172(6 Pt 2):2563-9.

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;58:2301-13.

Misseri R, Meldrum DR, Dinarello CA, Dagher P, Hile KL, Rink RC, et al. TNF-alpha mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling. Am J Physiol Renal Physiol. 2005;288:F406-11.

Hughes J, Johnson RJ. Role of Fas (CD95) in tubulointerstitial disease induced by unilateral ureteric obstruction. Am J Physiol. 1999;277(1 Pt 2):F26-32.

Choi YJ, Mendoza L, Rha SJ, Sheikh-Hamad D, Baranowska-Daca E, Nguyen V, et al. Role of p53-dependent activation of caspases in chronic obstructive uropathy: evidence from p53 null mutant mice. J Am Soc Nephrol Jasn. 2001;12:983-92.

Chung KH, Chevalier RL. Arrested development of the neonatal kidney following chronic ureteral obstruction. J Urol. 1996;155:1139-44.

Grande MT, Pérez-Barriocanal F, López-Novoa JM. Role of inflammation in túbulo-interstitial damage associated to obstructive nephropathy. J Inflamm Lond Engl. 2010;7:19.

Nørregaard R, Jensen BL, Topcu SO, Nielsen SS, Walter S, Djurhuus JC, et al. Cyclooxygenase type 2 is increased in obstructed rat and human ureter and contributes to pelvic pressure increase after obstruction. Kidney Int. 2006;70:872-81.

Kayanoki Y, Fujii J, Islam KN, Suzuki K, Kawata S, Matsuzawa Y, et al. The protective role of glutathione peroxidase in apoptosis induced by reactive oxygen species. J Biochem (Tokyo). 1996;119:817-22.

Chevalier RL, Thornhill BA, Wolstenholme JT. Renal cellular response to ureteral obstruction: role of maturation and angiotensin II. Am J Physiol. 1999;277(1 Pt 2):F41-7.

Chevalier RL, Smith CD, Wolstenholme J, Krajewski S, Reed JC. Chronic ureteral obstruction in the rat suppresses renal tubular Bcl-2 and stimulates apoptosis. Exp Nephrol. 2000;8:115-22.

Soliman SA, Shokeir AA, Mosbah A, Abol-Enein H, Barakat N, Abou-Bieh E, et al. Recoverability of renal function after relief of chronic partial unilateral ureteral obstruction: study of the effect of angiotensin receptor blocker (losartan). urology. 2010;75:848-52.

Zhou T-B, Qin Y-H, Zhou C, Lei F-Y, Zhao Y-J, Chen J, et al. Less expression of prohibitin is associated with increased caspase-3 expression and cell apoptosis in renal interstitial fibrosis rats. Nephrol Carlton Vic. 2012;17:189-96.

Harris KP, Klahr S, Schreiner G. Obstructive nephropathy: from mechanical disturbance to immune activation? Exp Nephrol. 1993;1:198-204.

Cachat F, Lange-Sperandio B, Chang AY, Kiley SC, Thornhill BA, Forbes MS, et al. Ureteral obstruction in neonatal mice elicits segment-specific tubular cell responses leading to nephron loss. Kidney Int. 2003;63:564-75.

Nguyen HT, Hsieh MH, Gaborro A, Tinloy B, Phillips C, Adam RM. JNK/SAPK and p38 SAPK-2 mediate mechanical stretch-induced apoptosis via caspase-3 and -9 in NRK-52E renal epithelial cells. Nephron Exp Nephrol. 2006;102:e49-61.

Original Research