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Effects of cell-type-specific expression of a pan-caspase inhibitor on renal fibrogenesis

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Abstract

Background

The caspase family of enzymes is grouped into two major sub-families, namely apoptotic and inflammatory caspases, which play central roles in the induction of apoptosis, regulation of inflammation and immunity, and cellular differentiation.

Methods

The role of caspase activation in tubular epithelium and interstitial cells of 3 lines of transgenic mice with obstructed nephropathy was examined: p35 mice bearing the pan-caspase inhibitor protein expressed by the p35 gene separated from the universal CAG promoter by a floxed STOP sequence were crossed with γGT.Cre and FSP1.Cre mice that express Cre recombinase in the cortical tubular epithelium and FSP1+ interstitial cells, respectively. The γGT.Cre;p35, FSP1.Cre;p35 and p35 control mice were then challenged with unilateral ureter obstruction (UUO).

Results

Proinflammatory parameters such as protein levels of active IL-1β subunit and mRNA levels of TNF-α and NOD-like receptor pyrin domain containing-3, and profibrogenic parameters such as interstitial matrix deposition and mRNA levels of fibronectin EIIIA isoform and α1 chain of procollagen type I in the kidneys were significantly increased at 7 days in the FSP1.Cre;p35- and p35-UUO mice, but not in the γGT.Cre;p35-UUO mice. These changes paralleled the numbers of apoptotic nuclei in tubules, but not in interstitial cells, and the protein levels of active caspase-3 subunit in the kidneys of FSP1.Cre;p35-, p35- and γGT.Cre;p35-UUO mice.

Conclusion

This study provides evidence of the critical role of caspase activation in the tubular epithelium, but not in FSP1+ interstitial cells, in apoptosis and inflammasome induction, leading to proinflammatory and profibrogenic processes in fibrous kidneys with UUO.

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Acknowledgments

We thank M. Fukuoka and T. Iso for their technical assistance. This research was supported in part by research grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and Asubio Pharma Co. Ltd.

Conflict of interest

All of the authors declared no conflicts of interests.

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Authors and Affiliations

  1. Department of Nephrology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan

    Tsutomu Inoue, Kouji Tomori, Hiromichi Suzuki & Hirokazu Okada

  2. Division of Project Research, Saitama Medical University Research Center of Genomic Medicine, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan

    Tsutomu Inoue, Takeru Kusano, Hiromichi Suzuki & Hirokazu Okada

  3. Department of General Internal Medicine, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan

    Takeru Kusano, Hidetomo Nakamoto & Hirokazu Okada

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  1. Tsutomu Inoue
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Correspondence to Hirokazu Okada.

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Inoue, T., Kusano, T., Tomori, K. et al. Effects of cell-type-specific expression of a pan-caspase inhibitor on renal fibrogenesis. Clin Exp Nephrol 19, 350–358 (2015). https://doi.org/10.1007/s10157-014-1011-0

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  • DOI: https://doi.org/10.1007/s10157-014-1011-0

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