Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System

Abstract

Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with 99m Tc-DTPA and 131 Ihippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.

Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice

“…23,24) On the other hand, heparin therapy is known to have a proteinuria-lowering effect, which cannot be explained via the RAA system. 25) van der Pijl et al reported that danaparoid, which is a mixture of sulfated glycosaminoglycans, significantly lowered proteinuria in type 1 diabetic nephropathy. 26) They suggested that danaparoid supplements the action of proteoglycans, rather than inhibiting factor Xa.…”

The ‘sweet’ and ‘bitter’ involvement of glycosaminoglycans in lung diseases: pharmacotherapeutic relevance

“…Administration of enoxaparin, which is a low‐molecular‐weight heparin, in patients with diabetic nephropathy exerted antiproteinuric effect not via the renin‐angiotensin‐aldosterone system, but apparently by inducing intrinsic alterations in the glomerular filter (Benck et al. , 2006).…”

Preclinical and clinical evidence of nephro- and cardiovascular protective effects of glycosaminoglycans

“…Enoxaparin, a low-molecular weight heparin, was also tested on patients with diabetic and non-diabetic glomerulopathies. The proteinuria-decreasing effect of this heparin was found not to be related to the renin-angiotensin system, and its glomerular filter-related effect was suggested [45]. …”

“…Angiotensin II inhibits HSPG expression in human podocytes [47] and heparins modulate AT-II signalling in glomerular cells [48], inhibiting aldosterone synthesis [49] and lowering proteinuria in diabetic patients [45], but this effect is less pronounced in other forms of proteinuric renal diseases and its relation to haemodynamic changes produced by RAS is not proven in clinical trials [45]. Of course, heparins are not easily administrable for chronic treatments.…”