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Abstract: FR-PO212

A Novel All-Trans Retinoic Acid Therapy Directly Suppresses Bone Morphogenetic Protein 4 in Mouse Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Tamaki, Masanori, Tokushima University, Tokushima, Japan
  • Tominaga, Tatsuya, Tokushima University, Tokushima, Japan
  • Fujita, Yui, Tokushima University, Tokushima, Japan
  • Murakami, Taichi, Tokushima University, Tokushima, Japan
  • Kishi, Seiji, Tokushima University, Tokushima, Japan
  • Abe, Hideharu, Tokushima University, Tokushima, Japan
  • Nagai, Kojiro, Tokushima University, Tokushima, Japan
  • Doi, Toshio, Tokushima University, Tokushima, Japan
Background

Diabetic nephropathy (DN) causes mesangial matrix expansion, resulting in glomerulosclerosis and renal failure. Collagen IV (COL4), a major component of the mesangial matrix, is positively regulated by bone morphogenetic protein 4 (BMP4)/suppressor of mothers against decapentaplegic (Smad1) signaling. Treatment with all-trans retinoic acid (ATRA), a potent ligand of the retinoic acid receptor (RAR), shows a beneficial effect on kidney disease; however, its effects on glomerular matrix expansion in DN remain unclear. RAR/retinoid X receptor (RXR) heterodimer binds directly with retinoic acid (RA) response element (RARE) and regulates transcription of various genes. In the present study, we investigated the therapeutic potential of retinoids in DN, focusing on the regulatory mechanism of BMP4.

Methods

Diabetes was induced with streptozotocin in 12-week-old male Crl:CD1(ICR) mice. One month later, we initiated intraperitoneal injection of ATRA (15 µg/gBW) or corn oil three times a week, from 16 to 24 weeks of age. ATRA or specific agonists for each subtype of RAR were added to cultured mouse mesangial cells from 1 nM to 1 µM with or without advanced glycation end products (AGE, 200 µg/ml) for 24 hours. We analyzed glomerular matrix expansion, BMP4/Smad1/COL4 axis, RAR/RXR binding capacity, and putative RAREs.

Results

Glomerular matrix expansion, associated with increased BMP4, phosphorylated Smad1, and COL4 expression, worsened in diabetic mice at 24 weeks of age. ATRA administration alleviated DN and downregulated BMP4, phospho-Smad1, and COL4. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor α (RARα) agonist significantly decreased BMP4 and COL4 expression, more so in AGE-treated cells. Genomic analysis suggested two putative RAREs for the mouse Bmp4 gene. ChIP analysis and reporter assays indicated a putative RARE of Bmp4, located 11488–11501 bp upstream of exon1A, which bound to RARα and RXR in animals’ kidney and in cultured cells, and the luminescence signal decreased after ATRA or RARα agonist addition.

Conclusion

ATRA suppressed BMP4 via binding of RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice. These findings provide a novel regulatory mechanism for treatment of DN.

Funding

  • Government Support - Non-U.S.