Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy.
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.
Rossini
Michele
M
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
Naito
Takashi
T
Yang
Haichun
H
Freeman
Michael
M
Donnert
Ellen
E
Ma
Li-Jun
LJ
Dunn
Stephen R
SR
Sharma
Kumar
K
Fogo
Agnes B
AB
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000528:radiation effects; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006025:Glycosaminoglycans; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C007858:glucuronyl glucosamine glycan sulfate; D003094:Collagen