Effect of retinoic acid in experimental diabetic nephropathy.
Although the pathogenetic mechanism of diabetic nephropathy has not been elucidated, an inflammatory mechanism has been suggested to contribute to its progression. Monocyte chemoattractant peptide (MCP)-1 attracts macrophages and T cells, and ultimately injures renal tissue. In early diabetic nephropathy, urinary excretion of MCP-1 was elevated, and increased as renal damage became more severe. Podocytes are expected to have an inflammatory role in diabetic nephropathy, as the surface expression of chemokine receptors such as CCR and CXCR on these cells has been recently reported. Although retinoid (retinal), a known anti-inflammatory agent, has been reported to be beneficial in some experimental models of renal disease, it has not been determined to prevent disease progression in diabetic nephropathy. We investigated the effects of all-trans retinoic acid on the production of MCP-1 under high glucose conditions in cultured mouse podocytes. We also evaluated whether all-trans retinoic acid inhibits inflammatory changes and improves renal function during the early stages of diabetic nephropathy in streptozotocin-induced diabetic rats. In cultured podocytes, high glucose stimuli rapidly upregulated the MCP-1 mRNA transcript and protein release. Treatment with retinoic acid tended to suppress the MCP-1 gene transcript, and significantly inhibited MCP-1 protein synthesis induced by high glucose stimulation. Urinary protein excretion and the urinary albumin : creatinine ratio (ACR) were significantly higher in diabetic rats 4 weeks after the induction of diabetes mellitus compared with control rats, and retinoic acid treatment markedly decreased both proteinuria and urinary ACR (proteinuria: 1.25+/-0.69 vs 0.78+/-0.72 mg/mgCr, P=0.056; urinary ACR: 0.47+/-0.25 vs 0.21+/-0.06 mg/mgCr, P=0.088). Urinary excretion of MCP-1 was rapidly increased 2 days after induction of diabetes mellitus in diabetic rats, and further increased until rats were 4 weeks of age, compared with control rats. Retinoic acid treatment resulted in 30% reduction of the urinary level of MCP-1 compared with vehicle-treated diabetic rats (119.3+/-74.2 vs 78.1+/-62.7 pg/mgCr, P=0.078). Immunohistochemistry revealed a significant increase in staining for MCP-1 and anti-monocyte/macrophage (ED-1) protein in the diabetic kidney, and retinoic acid treatment significantly suppressed intrarenal MCP-1 and ED-1 protein synthesis. In conclusion, podocytes are involved in the inflammatory reaction under diabetic circumstances, and these reactions were suppressed by retinoic acid. Retinoic acid also suppressed inflammatory changes in the diabetic rat kidney, and decreased proteinuria in diabetic rats. These results suggest that retinoic acid may have renoprotective effects in the early stages of diabetic nephropathy through an anti-inflammatory activity.
Han
Sang-Youb
SY
Department of Internal Medicine, Inje University, Ilsan-Gu, Koyang City, Kyungki-Do, Korea.
So
Gyeong-A
GA
Jee
Yi-Hwa
YH
Han
Kum-Hyun
KH
Kang
Young-Sun
YS
Kim
Hyoung-Kyu
HK
Kang
Shin-Wook
SW
Han
Dae-Suk
DS
Han
Jee-Young
JY
Cha
Dae-Ryong
DR
D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003401:Creatine / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D011507:Proteinuria / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
D018932:Chemokine CCL2; D012333:RNA, Messenger; D014212:Tretinoin; D013311:Streptozocin; D005947:Glucose; D003401:Creatine