Int J Biol Sci 2020; 16(3):435-446. doi:10.7150/ijbs.37550

Research Paper

Reno-protection of Urine-derived Stem Cells in A Chronic Kidney Disease Rat Model Induced by Renal Ischemia and Nephrotoxicity

Chao Zhang1,2, Sunil K. George1, Rongpei Wu1,3, Parth Udayan Thakker4, Mehran Abolbashari1, Tae-Hyoung Kim1,5, In Kap Ko1, Yuanyuan Zhang1✉, Yinghao Sun2, John Jackson1, Sang Jin Lee1, James J. Yoo1, Anthony Atala1

1. Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
2. Department of Urology, Changhai Hospital, the Second Military Medical University, 168 Changhai Road, Shanghai, People's Republic of China
3. Department of Urology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong, People's Republic of China.
4. Department of Urology, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, USA
5. Department of Urology, College of Medicine, Chung-Ang University, Seoul, South Korea

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Citation:
Zhang C, George SK, Wu R, Thakker PU, Abolbashari M, Kim TH, Ko IK, Zhang Y, Sun Y, Jackson J, Lee SJ, Yoo JJ, Atala A. Reno-protection of Urine-derived Stem Cells in A Chronic Kidney Disease Rat Model Induced by Renal Ischemia and Nephrotoxicity. Int J Biol Sci 2020; 16(3):435-446. doi:10.7150/ijbs.37550. Available from http://www.ijbs.com/v16p0435.htm

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Abstract

Purpose: Drug-induced nephrotoxicity can occur in patients with pre-existing renal dysfunction or renal ischemia, potentially leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Prompt treatment of CKD and the related side effects is critical in preventing progression to ESRD. The goal of this study was to demonstrate the therapeutic potential of urine-derived stem cells (USC) to treat chronic kidney disease-induced by nephrotoxic drugs and renal ischemia.

Materials and methods: Human USC were collected, expanded and characterized by flow cytometry. A CKD model was induced by creating an ischemia-reperfusion injury and gentamicin administration. Twenty-eight adult immunodeficient rats were divided into three groups: PBS-treated group (n=9), USC-treated group (n=9), and sham group with age-matched control animals (n=10). Cell suspension of USC (5 x 106 / 100µl / kidney) or PBS was injected bilaterally into the renal parenchyma 9 weeks after CKD model creation. Renal function was evaluated by collection blood and urine samples to measure serum creatinine and glomerulus filtration rate. The kidneys were harvested 12 weeks after cell injection. Histologically, the extent of glomerulosclerosis and tubular atrophy, the amount of collagen deposition, interstitial fibrosis, inflammatory monocyte infiltration, and expression of transforming growth factor beta 1 (TGF-ß1), and superoxide dismutase 1 (SOD-1) were examined.

Results: USC expressed renal parietal epithelial cells (CD24, CD29 and CD44). Renal function, measured by GFR and serum Cr in USC-treated group were significantly improved compared to PBS-treated animals (p<0.05). The degree of glomerular sclerosis and atrophic renal tubules, the amount of fibrosis, and monocyte infiltration significantly decreased in USC-treated group compared to the PBS group (p<0.05). The level of TGF-ß1 expression in renal tissues was also significantly lower in the PBS group, while the level of SOD-1 expression was significantly elevated in the USC group, compared to PBS group (p<0.05).

Conclusions: The present study demonstrates the nephron-protective effect of USC on renal function via anti-inflammatory, anti-oxidative stress, and anti-fibrotic activity in a dual-injury CKD rat model. This provides an alternative treatment for CKD in certain clinical situations, such as instances where CKD is due to drug-induced nephrotoxicity and renal ischemia.

Keywords: Urine-derived Stem Cell, Chronic Kidney Disease, Kidney degeneration