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Abstract: FR-PO928

Osteocrin Ameliorates Adriamycin-Induced Glomerular Injury

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Handa, Takaya, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Mori, Keita P., TMK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto City, Japan
  • Ishii, Akira, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Kanai, Yugo, Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • Yasoda, Akihiro, Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • Kuwabara, Takashige, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Mukoyama, Masashi, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Yokoi, Hideki, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Background

Natriuretic peptides including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) have cardioprotective effects through binding to natriuretic peptide (NP) receptors: Npr1 and Npr2. ANP or BNP exhibits potent renal effects in patients and animal models with heart failure. Recently a peptide, OSTN (osteocrin) is reported to bind to Npr3 which is a clearance receptor for NPs, and to prevent the worsening of congestive heart failure by increasing NPs with inhibition of degradation. However, the effect of OSTN on kidney function has not been elucidated yet. We hypothesized that OSTN has a renoprotective role by binding Npr3 to suppress clearance of NPs. We examined the role of OSTN in adriamycin (ADR) nephropathy, since podocytes are reported to express Npr3 in single-cell transcriptomics of the mouse kidney.

Methods

ADR was administered to wild-type and serum amyloid P (SAP) promoter-driven OSTN-transgenic (Tg) mice which showed plasma OSTN elevation, at dose of 8 mg/kg body weight via tail-vein injection. Mice were sacrificed at 4 weeks after ADR injection.

Results

There were no significant differences between wild-type mice and OSTN-Tg mice in systemic blood pressure, urinary volume, serum creatinine nor BUN. The body weight and body length of wild-type mice were significantly lower than those of OSTN-Tg mice (26.0 ± 1.0 g vs. 29.7 ± 0.6 g, p < 0.01; 9.5 ± 0.1 cm vs. 10.4 ± 0.1 cm, p < 0.0001, respectively). Increase of urinary albumin creatinine ratio of wild-type mice induced by ADR administration peaked at 2 weeks (165.6 ± 41.4μg/mgCr vs. 86.7 ± 7.6μg/mgCr, p < 0.05 ) and was significantly suppressed in that of OSTN-Tg mice at 4 weeks (91.5 ± 11.9μg/mgCr vs. 61.9 ± 3.0μg/mgCr, p < 0.05). Footprocess effacement observed in ADR-injected wild-type mice was ameliorated in ADR-administered OSTN-Tg mice, and thickness of glomerular basement membrane were significantly mitigated in OSTN-Tg mice in electron microscope (wild-type mice, 209 ± 12 nm vs. OSTN-Tg mice, 141 ± 3 nm, p < 0.0001).

Conclusion

These findings indicate that circulating OSTN has a reno- and podocyte-protective role in ADR nephropathy, probably through increase of natriuretic peptides on podocytes, and suggest that administration of OSTN could be a therapeutic option against podocyte injury.