Abstract: TH-PO706

Glomerulosclerosis Attenuated by Retinoic Acid through Bone Morphogenetic Protein 4 Suppression in Mice with Streptozotocin-Induced Diabetes

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

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

Mesangial matrix expansion, leading to glomerulosclerosis and renal dysfunction, is an important histologic change in diabetic nephropathy. A major component of mesangial matrix is collagen IV (COL4), which increases by bone morphogenetic protein 4 (BMP4)/mothers against decapentaplegic (Smad1) signaling. Retinoic acid (RA) attenuates glomerulosclerosis, although details are unclear. In general, RA receptor (RAR) combines directly with RA response element (RARE), although RARE is not determined around BMP4 gene. In the present study, we investigated the effect of RA on diabetic nephropathy, focusing on the regulatory mechanism of BMP4.

Methods

Male CD-1 mice were given streptozotocin at 12 weeks of age, followed a month later by intraperitoneal all-trans RA (atRA, 15 µg/gBW) or corn oil, each given thrice weekly. Animals’ kidneys were harvested after sacrifice at 24 weeks of age. atRA or specific agonists for each subtype of RAR were added to cultured CD-1 mice derived mesangial cells for 24 hours (from 1 nM to 10 µM). RAR binding capacity to RARE, suggested by genome analysis, was confirmed by ChIP analysis.

Results

Serum creatinine levels and urinary protein excretion increased in diabetic mice. Renal BMP4 and COL4 expression levels increased in diabetic mice. Glomerulosclerosis worsened in diabetic mice, and glomeruli phosphorylated Smad1 and COL4 levels increased. These findings were attenuated after atRA administration. In cultured mice mesangial cells, BMP4 and COL4 expression levels decreased after atRA addition or a low concentration addition of AM580, a specific agonist for RARα, but did not after a low concentration addition of either RARβ or RARγ agonist. ChIP analysis showed that a suggested RARE around mice Bmp4 gene combined with RARα after atRA addition.

Conclusion

atRA administration attenuated glomerulosclerosis and decreased BMP4 and COL4 expression levels in diabetic mice. Our study suggests that RARα combined with a novel RARE around the Bmp4 gene, plays an important role for regulating BMP4 expression, although further study is needed. These findings indicate that RA may provide a novel therapeutic mechanism for diabetic nephropathy.

Funding

  • Government Support - Non-U.S.