Int J Med Sci 2019; 16(1):180-188. doi:10.7150/ijms.27719

Research Paper

Nonselective Cyclooxygenase Inhibition Retards Cyst Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Min Zhang1, Manakan B. Srichai2,4, Min Zhao2, Jian Chen2, Linda S. Davis2, Guanqing Wu2,3, Matthew D. Breyer5, Chuan-Ming Hao1,2,4✉

1. Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
2. Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN
3. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN
4. VA Medical Center, Nashville, TN.
5. Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46225, USA

Abstract

Aim: Autosomal dominant polycystic kidney disease is one of the most common genetic renal diseases. Cyclooxygenase plays an important role in epithelial cell proliferation and may contribute to the mechanisms underlying cyst formation. The aim of the present study was to evaluate the role of cyclooxygenase inhibition in the cyst progression in polycystic kidney disease.

Method: Pkd2WS25/- mice, a murine model which harbors a compound cis-heterozygous mutation of the Pkd2 gene were used. Cyclooxygenase expression was assessed in both human and murine kidney specimens. Pkd2WS25/- mice were treated with Sulindac (a nonselective cyclooxygenase inhibitor) or vehicle for 8 months starting at three weeks age, and then renal cyst burden was assessed by kidney weight and volume.

Results: Cyclooxygenase-2 expression was up-regulated compared to control kidneys as shown by RNase protection in human polycystic kidneys and immunoblot in mouse Pkd2WS25/- kidneys. Cyclooxygenase-2 expression was up-regulated in the renal interstitium as well as focal areas of the cystic epithelium (p<0.05). Basal Cyclooxygenase-1 levels were unchanged in both immunohistochemistry and real-time PCR. Administration of Sulindac to Pkd2WS25/- mice and to control mice for 8 months resulted in reduced kidney weights and volume in cystic mice. Renal function and electrolytes were not significantly different between groups.

Conclusion: Thus treatment of a murine model of polycystic kidney disease with Sulindac results in decreased kidney cyst burden. These findings provide additional implications for the use of Cyclooxygenase inhibition as treatment to slow the progression of cyst burden in patients with polycystic kidney disease.

Keywords: ADPKD, COX2, PKD2, prostanoid, Sulindac

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How to cite this article:
Zhang M, Srichai MB, Zhao M, Chen J, Davis LS, Wu G, Breyer MD, Hao CM. Nonselective Cyclooxygenase Inhibition Retards Cyst Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease. Int J Med Sci 2019; 16(1):180-188. doi:10.7150/ijms.27719. Available from http://www.medsci.org/v16p0180.htm