Sulodexide decreases albuminuria and regulates matrix protein accumulation in C57BL/6 mice with streptozotocin-induced type I diabetic nephropathy.
OBJECTIVE
Sulodexide is a mixture of glycosaminoglycans that may reduce proteinuria in diabetic nephropathy (DN), but its mechanism of action and effect on renal histology is not known. We investigated the effect of sulodexide on disease manifestations in a murine model of type I DN.


METHODS
Male C57BL/6 mice were rendered diabetic with streptozotocin. After the onset of proteinuria, mice were randomized to receive sulodexide (1 mg/kg/day) or saline for up to 12 weeks and renal function, histology and fibrosis were examined. The effect of sulodexide on fibrogenesis in murine mesangial cells (MMC) was also investigated.


RESULTS
Mice with DN showed progressive albuminuria and renal deterioration over time, accompanied by mesangial expansion, PKC and ERK activation, increased renal expression of TGF-β1, fibronectin and collagen type I, III and IV, but decreased glomerular perlecan expression. Sulodexide treatment significantly reduced albuminuria, improved renal function, increased glomerular perlecan expression and reduced collagen type I and IV expression and ERK activation. Intra-glomerular PKC-α activation was not affected by sulodexide treatment whereas glomerular expression of fibronectin and collagen type III was increased. MMC stimulated with 30 mM D-glucose showed increased PKC and ERK mediated fibronectin and collagen type III synthesis. Sulodexide alone significantly increased fibronectin and collagen type III synthesis in a dose-dependent manner in MMC and this increase was further enhanced in the presence of 30 mM D-glucose. Sulodexide showed a dose-dependent inhibition of 30 mM D-glucose-induced PKC-βII and ERK phosphorylation, but had no effect on PKC-α or PKC-βI phosphorylation.


CONCLUSIONS
Our data demonstrated that while sulodexide treatment reduced proteinuria and improved renal function, it had differential effects on signaling pathways and matrix protein synthesis in the kidney of C57BL/6 mice with DN.
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. ssyyung@hku.hk
Susan
S
Yung
Mel K M
MK
Chau
Qing
Q
Zhang
Chen Zhu
CZ
Zhang
Tak Mao
TM
Chan
D000419:Albuminuria / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006025:Glycosaminoglycans / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D006025:Glycosaminoglycans; C007858:glucuronyl glucosamine glycan sulfate; D005947:Glucose