Abstract
The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches.
Highlights
Diabetic nephropathy (DN) is a microvascular complication of diabetes leading to end‐stage renal disease that is difficult to handle despite strict glycaemic control and targeted therapies, indicating the paramount importance to develop novel treatments
Major players in the diabetes‐associated renal fibrosis include members of the plasminogen (Plg)‐plasmin system that consists of the circulating zymogen Plg and its activators including the urokinase‐type plasminogen activator, a secreted protease that, through the binding to its receptor, converts Plg into plasmin that promotes extracellular matrix (ECM) degradation either directly or indirectly through the activation of metalloproteinases (MMPs).[8] uPA is a secreted protease, while uPAR is expressed by glomerular cells, resident fibroblasts and cells of the collecting ducts.[9]
The interaction between uPA and uPAR is mediated by several membrane proteins including the formyl peptide receptors (FPRs) that are G protein‐coupled receptors involved in different pathophysiological processes,[8] little is known about their possible involvement in diabetic kidney disease
Summary
Diabetic nephropathy (DN) is a microvascular complication of diabetes leading to end‐stage renal disease that is difficult to handle despite strict glycaemic control and targeted therapies, indicating the paramount importance to develop novel treatments. The interaction between uPA and uPAR is mediated by several membrane proteins including the formyl peptide receptors (FPRs) that are G protein‐coupled receptors involved in different pathophysiological processes,[8] little is known about their possible involvement in diabetic kidney disease. Protein levels of uPA, uPAR and FPRs were measured in kidney extracts, while transcripts of FPRs were determined in isolated glomeruli, before and after UPARANT treatment. UPARANT action on αvβ[3] integrin and Rac‐1 was explored and its possible effects on ECM components including fibronectin, collagen I and collagen IV were considered as an indirect evidence of UPARANT role in the fibrotic process that was directly evaluated at the histological level. We assessed the effects of UPARANT on DN‐associated morphological alterations of the glomerulus including a transmission electron microscopy (TEM) evaluation of the filtration barrier
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