Retinoids as a potential treatment for experimental puromycin‐induced nephrosis

• Published in: British journal of pharmacology Vol. 139; no. 4; pp. 823 - 831
• Main Authors: Moreno‐Manzano, V, Mampaso, F, Sepúlveda‐Muñoz, J C, Alique, M, Chen, S, Ziyadeh, F N, Iglesias‐de la Cruz, M C, Rodríguez, J, Nieto, E, Orellana, J M, Reyes, P, Arribas, I, Xu, Q, Kitamura, M, Lucio Cazana, F J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-2003; Nature Publishing
• Subjects: adhesion molecules; Administration, Oral; Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Cell Culture Techniques; Cell Movement; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL2 - biosynthesis; Disease Models, Animal; Drug Combinations; Epithelial Cells - drug effects; Epithelial Cells - ultrastructure; Female; Fibronectins - antagonists & inhibitors; Fibronectins - biosynthesis; Food; inflammation; Injections, Intraperitoneal; kidney; Kidney Glomerulus - drug effects; Kidney Glomerulus - ultrastructure; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - ultrastructure; Medical sciences; Mice; nephrosis; Nephrosis - chemically induced; Nephrosis - pathology; Nephrosis - prevention & control; podocyte; proteinuria; Proteinuria - chemically induced; Proteinuria - prevention & control; Puromycin aminonucleoside; Puromycin Aminonucleoside - administration & dosage; Puromycin Aminonucleoside - adverse effects; Rats; Rats, Wistar; Retinoids - administration & dosage; Retinoids - pharmacokinetics; Retinoids - therapeutic use; Time Factors; tretinoin (all‐trans retinoic acid); tretinoin (all-trans retinoic acid); kidney; adhesion molecules; inflammation; proteinuria; podocyte; nephrosis; Puromycin aminonucleoside
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705311

Puromycin aminonucleoside (PAN)‐induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic‐range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types.
Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all‐trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte.
Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti‐inflammatory effect of tRA was evidenced by the inhibition of PAN‐induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein‐1. TUNEL assays showed that tRA inhibited the PAN‐induced apoptosis of cultured differentiated mouse podocytes.
We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.
British Journal of Pharmacology (2003) 139, 823–831. doi:10.1038/sj.bjp.0705311