DN occurs in up to 40% of diabetic patients and is one of the leading causes of ESRD. The approach to treating DN includes the pursuit of normoglycemia and normotension, but the search for new therapeutic strategies to prevent and treat this complication of diabetes is warranted because strict metabolic control can be difficult to achieve in many cases.
The search for new strategies includes seeking molecular targets and, in this perspective, several studies have demonstrated the involvement of HPSE in the pathogenesis of DN , at both tubular and glomerular levels  HPSE could therefore be a pharmacological target for treating DN. To date, several HPSE inhibitors have been identified, some of which are now being tested in clinical trails. Most of them are modified heparins or LMWHs .
GAGs like sulodexide have a favorable effect in DN. A number of mechanisms have been suggested to explain the nephroprotective effect of GAGs and sulodexide , including a direct inhibitory effect on HPSE , which reportedly increases in the glomeruli of DN patients . The chemical composition of sulodexide gives the product an HPSE inhibiting action .
Almost all the above hypothesized mechanisms have been demonstrated at glomerular level, but one of the pathological hallmarks of the progression of kidney disease is tubulo-interstitial fibrosis. The severity of this condition has proved to be much more closely related to the risk of ESRD than glomerular lesions . The accumulation of extracellular matrix in the interstitium is sustained by the transformation of tubular epithelial cells into myofibroblasts (EMT) and this event is triggered by several growth factors and different signaling pathways .
We recently showed that HPSE is involved in the regulation of EMT of tubular cells induced by FGF-2. HPSE is necessary for FGF-2 to activate the PI3K/AKT pathway leading to EMT, and for FGF-2 to produce an autocrine loop by down-regulating SDC1 and up-regulating MMP9 and the same HPSE .
Here we demonstrate that sulodexide – a combination of GAGs composed of heparin-like (80%) and dermatan fractions (20%) that is currently used to treat thrombotic disorders and DN - is an effective HPSE inhibitor capable of preventing FGF-2-induced EMT in renal tubular cells.
Sulodexide can inhibit HPSE at therapeutic concentrations : its IC50 is 5 μg/ml, and 20 μg/ml of sulodexide suffice to completely inhibit HPSE activity. Investigating the different power of the two ingredients in sulodexide, we found H2046 (and parnaparin) a very effective inhibitor of HPSE, whereas D2047 (and DS) had only a weak inhibitory action. The results of tests on combinations containing different proportions of LMWHs and dermatan sulfates confirmed that sulodexide’s HPSE-inhibiting effect is due exclusively to the heparin component, with no synergistic effect between the two ingredients.
These data are consistent with the results obtained by Naggi et al  using a different experimental approach. Notably, the Vlodavsky group has shown that sulodexide had a mild inhibitory effect on heparanase enzymatic activity at a concentration of 1 μg/ml, achieving a 50% inhibition with 5 μg/ml, and complete inhibition with 50 μg/ml (personal communication).
As expected, sulodexide - being an HPSE inhibitor - also prevented the overexpression of the mesenchymal markers αSMA, VIM and FN, i.e. it prevented the human renal tubular cell EMT induced by FGF-2.
Sulodexide prevented the increase in HPSE and MMP9 expression and activity and the associated SDC1 reduction that are triggered by FGF-2 in tubular cells, which means that sulodexide switched off the autocrine loop that FGF-2 activates to fuel its signal.
The fact that FGF-2 induced cell migration was inhibited by sulodexide and H2046 (and parnaparin), but not by D2047 (and DS), further confirms that sulodexide prevents FGF-2-induced EMT through its HPSE inhibiting activity.