Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy

Hyung Sook Kim; Jae Seob Lee; Hong Kyung Lee; Eun Jae Park; Hye Won Jeon; Yu Jeong Kang; Tae Yong Lee; Kyung Suk Kim; Sang-Cheol Bae; Ji Hyun Park; Sang-Bae Han

doi:10.4110/in.2018.19.e36

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Kim, Lee, Lee, Park, Jeon, Kang, Lee, Kim, Bae, Park, and Han: Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy

Brief Communication

Immune Netw 2019;19(5):e36.

Published online: 4 October 2019

DOI: https://doi.org/10.4110/in.2018.19.e36

Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy

Hyung Sook Kim^1,^†, Jae Seob Lee^1,^†, Hong Kyung Lee¹, Eun Jae Park¹, Hye Won Jeon¹, Yu Jeong Kang¹, Tae Yong Lee^1,², Kyung Suk Kim², Sang-Cheol Bae³, Ji Hyun Park^4,, Sang-Bae Han^1,^*

¹College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea

²Bioengineering Institute, Corestem Inc., Seoul 04763, Korea

³Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea

⁴College of Pharmacy, Korea University, Sejong 30019, Korea

^*Correspondence to Sang-Bae Han College of Pharmacy, Chungbuk National University, 194-21, Osongsaengmyeong 1-ro, Heungdeok-gu, Cheongju 28160, Korea. E-mail: shan@chungbuk.ac.kr

Ji Hyun Park College of Pharmacy, Korea University, 2511, Sejong-ro, Sejong 30019, Korea. E-mail: pharmerpark@korea.ac.kr

^† These authors contribute equally to this work.

Conflict of Interest Kim KS and Lee TY are employees of Corestem Inc. and others declare no conflict of interest.

Received 18 September 2019 Revised 27 September 2019 Accepted 2 October 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Mesenchymal stem cells (MSCs) ameliorate the renal injury in Adriamycin (ADR)-induced nephropathy, but the mechanisms underlying their efficacy remain incompletely understood. In this study, we demonstrated that MSCs increased the survival, recovered body weight loss, and decreased proteinuria and serum creatinine levels in ADR-treated mice. MSCs also prevented podocyte damage and renal fibrosis by decreasing the expression of fibronectin, collagen 1α1, and α-smooth muscle actin. From a mechanistic perspective, MSCs inhibited renal inflammation by lowering the expression of CCL4, CCL7, CCL19, IFN-α/β, TGF-β, TNF-α, and chitinase 3-like 1. In summary, our data demonstrate that MSCs improve renal functions by inhibiting renal inflammation in ADR-induced nephropathy.

Keywords: Mesenchymal stem cells, Inflammation, Podocytes, Fibrosis

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Figure 1.

MSCs ameliorate renal injury in ADR-treated mice. (A-G) Male BALB/c mice were intravenously injected with 10 mg/kg of ADR on day 0, and MSCs (1×10⁶ cells/mouse) on days 7 and 14 (arrows). Mice were sacrificed on day 28 to determine (A) survival rate, (B) body weight, (C) kidney morphology and weight, (D) proteinuria level, and (E) serum creatinine level. (F) Kidney sections were stained with PAS or Masson's trichrome stains. The amounts of glycoprotein (arrow ①), the size of capsular spaces (arrow ②), and the size of tubules (arrow ③), and the amounts of collagens (arrow ④) in the glomeruli were examined. Glomerular size, glomerular sclerotic index, and tubular damage score are presented. (G) Expression of the podocyte injury marker desmin was measured by immunohistochemistry. Each group are presented as CON (chemically-untreated control mice; n=6), ADR (ADR-treated mice; n=6), and ADR+MSC (ADR and MSC-treated mice; n=7), respectively. (H) Podocytes were isolated from normal BALB/c mice and were cultured with MSCs and/or 0.5 µg/ml of ADR for 24 h. Gene and protein expression of apoptotic (BAX) and anti-apoptotic (Bcl-2) molecules were measured by RT-qPCR and Western blot, respectively. * p<0.05 CON versus ADR; ^† p<0.05 ADR versus ADR+MSC; ^‡ p<0.05.

Figure 2.

MSCs inhibit renal inflammation in ADR-treated mice. (A-C, E, and F) Male BALB/c mice were intravenously injected with 10 mg/kg of ADR on day 0, and MSCs (1×10⁶ cells/mouse) on days 7 and 14. Mice were sacrificed on day 28. The amounts of mRNA of cytokines (A), CHI3L1 (B), chemokines (E), and extracellular proteins, such as fibronectin, Col1α1, and α-SMA (F) were measured by RT-qPCR. (C) The level of CHI3L1 in serum was measured by ELISA. Each group are presented as CON (chemically-untreated control mice; n=6), ADR (ADR-treated mice; n=6), and ADR+MSC (ADR and MSC-treated mice; n=7), respectively. (D) ADR was injected to WT male C57BL/6 or CHI3L1 KO mice (C57BL/6 background) on day 0 and proteinuria level was measured on day 28. Each group are presented as CON (chemically-untreated control mice; n=4) and ADR (ADR-treated mice; n=4), respectively. * p<0.05 CON versus ADR; ^† p<0.05 ADR versus ADR+MSC; ^‡ p<0.05.

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