Sulodexide ameliorates early but not late kidney disease in models of radiation
nephropathy and diabetic nephropathy.
Authors Rossini M, Naito T, Yang H, Freeman M, Donnert E, Ma LJ, Dunn SR, Sharma K, Fogo
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.

Investigators with authorship
Kumar SharmaUniversity of California San Diego