Regulation of heparanase by albumin and advanced glycation end products in proximal tubular cells

Biochim Biophys Acta. 2011 Aug;1813(8):1475-82. doi: 10.1016/j.bbamcr.2011.05.004. Epub 2011 May 12.

Abstract

Diabetic nephropathy is one of the main causes of end-stage renal disease, in which the development of tubular damage depends on factors such as high glucose levels, albuminuria and advanced glycation end-product. In this study, we analyzed the involvement of heparanase, a heparan sulfate glycosidase, in the homeostasis of proximal tubular epithelial cells in the diabetic milieu. In vitro studies were performed on a wild-type and stably heparanase-silenced adult tubular line (HK2) and HEK293. Gene and protein expression analyses were performed in the presence and absence of diabetic mediators. Albumin and advanced glycation end-product, but not high glucose levels, increased heparanase expression in adult tubular cells via the AKT/PI3K signaling pathway. This over-expression of heparanase is then responsible for heparan sulfate reduction via its endoglycosidase activity and its capacity to regulate the heparan sulfate-proteoglycans core protein. In fact, heparanase regulates the gene expression of syndecan-1, the most abundant heparan sulfate-proteoglycans in tubular cells. We showed that heparanase is a target gene of the diabetic nephropathy mediators albumin and advanced glycation end-product, so it may be relevant to the progression of diabetic nephropathy. It could take part in several processes, e.g. extracellular-matrix remodeling and cell-cell crosstalk, via its heparan sulfate endoglycosidase activity and capacity to regulate the expression of the heparan sulfate-proteoglycan syndecan-1.

MeSH terms

  • Albumins / metabolism*
  • Base Sequence
  • Cell Line
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism
  • Glucose / metabolism
  • Glucuronidase / antagonists & inhibitors
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • Glycation End Products, Advanced / metabolism*
  • HEK293 Cells
  • Heparitin Sulfate / metabolism
  • Homeostasis
  • Humans
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / metabolism
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Serum Albumin / metabolism
  • Serum Albumin, Bovine / metabolism
  • Syndecan-1 / genetics
  • Syndecan-1 / metabolism
  • Transcriptional Activation

Substances

  • Albumins
  • Glycation End Products, Advanced
  • RNA, Messenger
  • RNA, Small Interfering
  • SDC1 protein, human
  • Serum Albumin
  • Syndecan-1
  • glycosylated serum albumin
  • Serum Albumin, Bovine
  • Heparitin Sulfate
  • heparanase
  • Glucuronidase
  • Glucose