Heparanase: another renal player controlled by vitamin D

Abstract

To take effect, 1,25-D 3 needs to bind to vitamin D receptor (VDR), a nuclear receptor expressed in various organs (including the kidney) that acts as a transcription factor, regulating the gene expression of proteins implicated in calcium and phosphate transportation [2]. Finding that VDR is also expressed in cells uninvolved in mineral metabolism suggests, however, that vitamin D has a much broader range of activities. In fact, VDR can bind to genes involved in cell proliferation and differentiation. Vitamin D has a modulating effect on inflammation and on the immune and endocrine systems, including the renin-angiotensin-aldosterone (RAA) axis and insulin resistance [3]. The conviction that these general activities of vitamin D may be of paramount importance is supported by epidemiological studies showing a strong association between low vitamin D levels and a higher risk of cardiovascular, infectious, autoimmune and neurodegenerative disorders, diabetes and cancer, both in healthy people and in patients with chronic kidney disease (CKD) [4,5]. Interventional studies also support this impression, and supplementation with vitamin D and its analogues seems to be associated with a lower mortality [5].Interestingly, supplementation with vitamin D and its analogues may have kidney-protecting effects too, as suggested by a decrease in urinary protein levels [6]. Proteinuria is the most powerful predictor of unfavourable outcome in most forms of CKD, and its reduction is considered to be a surrogate endpoint in trials investigating the effects of experimental drugs on the progression of CKD to end-stage renal disease (ESRD) [7]. Vitamin D may exert its nephroprotective action by modulating the RAA system, which plays a vital part in regulating blood pressure and volume, electrolyte homeostasis and the intraglomerular pressure that drives proteinuria. Drugs targeting the RAA system -the angiotensin-converting enzyme inhibitors (ACEi) and the angiotensin receptor blockers (ARB) -are believed to reduce glomerular filtration, and consequently also proteinuria, by reducing the intraglomerular pressure, and the reduction in proteinuria

Evaluation of the C-domain of heparanase during AGE-induced macrophage inflammatory response

“…Heparanase (HPA), a unique and specific functional endo-β-D-glucuronidase, cleaves heparan sulfate (HS) chains for remodeling of extracellular matrix and regulation of the release of many HS-linked molecules such as growth factors, and cytokines (4,5). Previous findings showed that deletion of the C-domain of HPA generated enzymatically inactive HPA (6).…”