Urinary Smad1 Is a Novel Marker to Predict Later Onset of Mesangial Matrix Expansion in Diabetic Nephropathy

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 6; pp. 1712 - 1722
• Main Authors: Mima, Akira, Arai, Hidenori, Matsubara, Takeshi, Abe, Hideharu, Nagai, Kojiro, Tamura, Yukinori, Torikoshi, Kazuo, Araki, Makoto, Kanamori, Hiroshi, Takahashi, Toshikazu, Tominaga, Tatsuya, Matsuura, Motokazu, Iehara, Noriyuki, Fukatsu, Atsushi, Kita, Toru, Doi, Toshio
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.06.2008
• Subjects: Acids; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Biomarkers - urine; Biopsy; Creatinine; Diabetes; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Experimental - urine; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - urine; Diabetic nephropathy; Extracellular matrix; Glomerular Mesangium - pathology; Glomerular Mesangium - physiopathology; Glomerulonephritis; Glucose; Growth factors; Imidazoles - therapeutic use; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Laboratory animals; Male; Measurement; Mice; Mice, Inbred C57BL; Microscopy; Morphology; Rats; Rats, Sprague-Dawley; Research design; Risk factors; Rodents; Smad proteins; Smad1 Protein - urine; Tetrazoles - therapeutic use; Japan
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db07-1726

Urinary Smad1 Is a Novel Marker to Predict Later Onset of Mesangial Matrix Expansion in Diabetic Nephropathy Akira Mima 1 , Hidenori Arai 2 , Takeshi Matsubara 1 , Hideharu Abe 3 , Kojiro Nagai 4 , Yukinori Tamura 5 , Kazuo Torikoshi 1 , Makoto Araki 1 , Hiroshi Kanamori 1 , Toshikazu Takahashi 3 , Tatsuya Tominaga 3 , Motokazu Matsuura 3 , Noriyuki Iehara 1 , Atsushi Fukatsu 1 , Toru Kita 6 and Toshio Doi 3 1 Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan 2 Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan 3 Department of Clinical Biology and Medicine, Tokushima University Graduate School of Medicine, Tokushima, Japan 4 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 5 Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan 6 Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Corresponding author: Hidenori Arai, MD, PhD, Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: harai{at}kuhp.kyoto-u.ac.jp Abstract OBJECTIVE— We reported that Smad1 is a key transcriptional factor for mesangial matrix expansion in diabetic nephropathy. In this study, we examined whether urinary Smad1 in an early phase of diabetes can predict later development of glomerulosclerosis in diabetic nephropathy and how an angiotensin II type 1 receptor blocker (ARB) can modulate structural changes and urinary markers. RESEARCH DESIGN AND METHODS— Smad1 and albumin in the urine were examined 4 weeks after injection of streptozotocin in 48 rats or 6 weeks of diabetes in db/db mice. Their renal pathology was analyzed after 20 weeks in rats or 12 weeks in mice. Among 48 diabetic rats 7 rats were treated with olmesartan for 20 weeks. RESULTS— Urinary Smad1 of diabetic rats at 4 weeks was nicely correlated with mesangial matrix expansion at 24 weeks ( r = 0.70, P < 0.001), while albuminuria showed a weaker association ( r = 0.31, P = 0.043). Olmesartan treatment significantly ameliorated glomerulosclerosis and dramatically decreased urinary Smad1 (from 3.9 ± 2.9 to 0.3 ± 0.3 ng/mg creatinine, P < 0.05). In db/db mice, urinary Smad1 at 6 weeks was also significantly correlated with mesangial expansion at 18 weeks. In contrast, there was no change in urinary Smad1 in control diabetic rats or mice. CONCLUSIONS— The increase of urinary Smad1 in the early stages of diabetes is correlated with later development of glomerulosclerosis in two rodent models. These data indicate that urinary Smad1 could be a novel predictor for later onset of morphological changes and can be used to monitor the effect of ARBs in diabetic nephropathy. ARB, angiotensin II type 1 receptor blocker Ccr, creatinine clearance ECM, extracellular matrix ELISA, enzyme-linked immunosorbent assay PAS, periodic acid Schiff PASM, periodic acid silver methenamine STZ, streptozotocin Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 19 February 2008. DOI: 10.2337/db07-1726. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1726 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 1459 . Accepted February 8, 2008. Received December 10, 2007. DIABETES