| Authors |
Rossini M, Naito T, Yang H, Freeman M, Donnert E, Ma LJ, Dunn SR, Sharma K, Fogo
AB
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| Submitted By |
Kumar Sharma on 8/12/2010 |
| Status |
Published |
| Journal |
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association |
| Year |
2010 |
| Date Published |
6/1/2010 |
| Volume : Pages |
25 : 1803 - 1810 |
| PubMed Reference |
20061322 |
| Abstract |
BACKGROUND: Sulodexide is a glycosaminoglycan with anticoagulant and
antithrombotic activities. Although sulodexide reduced albuminuria in patients
with type 1 and type 2 diabetes, long-term effects on chronic renal injury are
not established. We investigated sulodexide effects and mechanisms in a rat
radiation nephropathy model and in the db/db mouse model of diabetic kidney
disease. METHODS: Sprague-Dawley rats received kidney radiation and were treated
as follows: 15 mg/kg/day sulodexide s.c., 6 day/week (SUL) or no treatment
(CONT). Subsets of animals were sacrificed after 8 weeks and 12 weeks. Blood
pressure, serum creatinine, creatinine clearance (CrCl) and urinary protein
excretion were measured every 4 weeks. Sclerosis and plasminogen activator
inhibitor-1 (PAI-1) expression were assessed at 8 and 12 weeks, and collagen I,
total collagen content and phospho-smad-2 expressions were determined at 12
weeks. Twelve-week-old db/db mice received sulodexide as above or vehicle.
Albuminuria and CrCl were assessed at intervals till sacrifice at week 9 with
assessment of urinary transforming growth factor-beta (TGF-beta) and glomerular
lesions. RESULTS: Blood pressure, serum creatinine and CrCl were not different
in radiation rat CONT vs SUL at any time. Proteinuria was significantly lower in
SUL compared to CONT at 4 and 8 weeks but not at 12 weeks. Sclerosis and PAI-1
expression trended lower in SUL vs CONT at 8 weeks. There was no difference
between the groups in sclerosis, collagen I mRNA, total collagen content or
PAI-1 expression at 12 weeks. Phospho-smad 2 expression was significantly
decreased in SUL compared to CONT at 12 weeks. Db/db mice with or without SUL
showed no difference in urinary albumin/creatinine ratio, urine TGF-beta or
mesangial matrix expansion. CONCLUSIONS: Our data show that sulodexide can
reduce the early, but not late, proteinuria in radiation nephropathy in rats. In
addition, sulodexide did not affect urine TGF-beta established albuminuria or
mesangial matrix expansion in a chronic model of diabetic kidney disease in
mice. Although sulodexide may affect TGF-beta activation in radiation
nephropathy, this effect appeared insufficient in this model to inhibit the
expressions of PAI-1 and collagen and reduce accumulation of extracellular
matrix. These results may explain in part its lack of efficacy in recent
clinical trials of chronic kidney disease.
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