Kidney Week

Abstract: SA-PO305

Deletion of Matrix Metalloproteinase-10 Ameliorates Aldosterone-Induced Glomerular Injury in Guanylyl Cyclase-A Knockout Mice

Session Information

• Cellular Crosstalk in Glomerular Diseases - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Osaki, Keisuke, Kyoto University Graduate School of Medicine, Kyoto, Japan

Keisuke Osaki,

• Kato, Yukiko, Kyoto University Graduate School of Medicine, Kyoto, Japan

Yukiko Kato,

• Toda, Naohiro, Kansai Electric Power Hospital, Osaka, OSAKA-FU, Japan

Naohiro Toda,

• Ishii, Akira, Kyoto University Graduate School of Medicine, Kyoto, Japan

Akira Ishii,

• Mori, Keita P., Kyoto University Graduate School of Medicine, Kyoto, Japan

Keita P. Mori,

• Ohno, Shoko, Kyoto University Graduate School of Medicine, Kyoto, Japan

Shoko Ohno,

• Mori, Kiyoshi, School of Pharmaceut Sci, University of Shizuoka, Shizuoka, Japan

Kiyoshi Mori,

• Kasahara, Masato, Institute for Clinical and Translational Science Nara Medical University Hospital, Kashihara, Japan

Masato Kasahara,

• Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Masashi Mukoyama,

• Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Motoko Yanagita,

• Yokoi, Hideki, Kyoto University Graduate School of Medicine, Kyoto, Japan

Hideki Yokoi,

Background

Recently, we and others have unveiled the novel renal function of natriuretic peptide receptor/guanylyl cyclase-A (GC-A) system on antagonizing aldosterone-induced podocyte injury as well as the conventional effects on natriuresis and reducing blood pressure. We previously investigated uninephrectomized, aldosterone-infused, and high salt diet-fed (ALDO) systemic GC-A knockout (KO) mice, resulting in hypertension, massive albuminuria, mesangial expansion and podocyte injury. However, genes involved in glomerular injury are elusive.

Methods

To identify responsible genes for podocyte injury, we compared glomerular mRNAs from ALDO control mice with ALDO systemic GC-A KO mice using microarray. Furthermore, we examined the role of the identified gene using its KO mice. We performed immunofluorescence study for an identified protein.

Results

Microarray analysis revealed that matrix metalloproteinase-10 (MMP-10) was upregulated more than 40 times in glomeruli of ALDO GC-A KO mice. To investigate the role of MMP-10, we generated double KO (DKO) mice for systemic GC-A and systemic MMP-10. ALDO systemic GC-A and MMP-10 DKO mice showed 80% reduction of albuminuria (4657μg/mgCr vs 24516μg/mgCr, p<0.05), and amelioration of podocyte injury demonstrated by improvement of foot process effacement and preservation of podocyte number, compared with ALDO systemic GC-A KO mice. Glomerular mRNA expression of extracellular matrix-related genes such as Tgfb1, Ctgf, and Col4a3 was upregulated in ALDO GC-A KO mice, and the upregulation was canceled by deletion of MMP-10. Immunofluorescence study revealed that MMP-10 expression was pronounced mainly in glomerular cells in ALDO GC-A KO mice. MMP-10 expression was also increased in proliferative lesions of human glomerular diseases such as Lupus nephritis, ANCA related nephritis, and IgA nephritis. In vitro, mRNA expression of MMP-10 was increased in human podocytes with TNF-α or TGF-β stimulation.

Conclusion

These results suggest that MMP-10 plays a crucial role in aldosterone- induced podocyte injury in GC-A KO mice, and can be a potential new target for treating kidney diseases.