Urinary Smad1 is a novel marker to predict later onset of mesangial matrix expansion in diabetic nephropathy.
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.


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.
Mima
Akira
A
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Arai
Hidenori
H
Matsubara
Takeshi
T
Abe
Hideharu
H
Nagai
Kojiro
K
Tamura
Yukinori
Y
Torikoshi
Kazuo
K
Araki
Makoto
M
Kanamori
Hiroshi
H
Takahashi
Toshikazu
T
Tominaga
Tatsuya
T
Matsuura
Motokazu
M
Iehara
Noriyuki
N
Fukatsu
Atsushi
A
Kita
Toru
T
Doi
Toshio
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D005920:Glomerular Mesangium / Q000473:pathology* / Q000503:physiopathology; D007093:Imidazoles / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D051898:Smad1 Protein / Q000652:urine*; D013777:Tetrazoles / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D007093:Imidazoles; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C497400:Smad1 protein, rat; D013777:Tetrazoles; C437965:olmesartan