# The role ofglycosaminoglycan N-sulfation in glomerular biology/pathobiology

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2020 · $514,289

## Abstract

The incidence of chronic kidney disease (CKD) in adults 60 and older increased from 18.8 to 24.5
percent between 1988-1994; currently this has risen to 26 percent. The mortality rate resulting from end
stage renal disease (ESRD) is 150/1000 individuals in the population. In light of this information, it becomes
important to identify key pathways that contribute to the development and the progression of CKD/ESRD.
Over the past decade it has become recognized in the renal field that the glomerular podocyte is a key and
critical determinant in the regulation of glomerular homeostasis. Recent studies have shown that the β1
integrins, primarily the α3β1 integrin heterodimer, mediate podocyte/glomerular basement membrane (GBM)
interactions. It is also well known that integrin affinity for its respective ligand can be modified by the activity of
intracellular signaling pathways (inside-out signaling or affinity modulation) and/or by the activity of cell
surface co-receptors. Previous studies in other cell systems have shown that several members of the
syndecan (Sdc) family of cell surface proteoglycans serve as cell adhesion co-receptors, which function
alongside integrins in the formation of focal adhesions in most cells. Unlike integrins, the binding of Sdcs to
their respective ligands is mediated primarily by the heparan sulfate glycosaminoglycan chains (HS) that are
covalently attached to Sdc core proteins. Because the HS chains are capable of engaging/binding multiple
ligands along the length of their chains, the interactions mediated by Sdc are promiscuous (many different
ligand targets) and multiplexed (many ligand binding sites per HS chain). There is a degree of specificity in
the HS-ligand interactions that is derived from the post-assembly modifications to HS, one key modification is
the modification of the nascent carbohydrate chain during its assembly by the enzyme NDST1 (N-
deacetylase-N-Sulfotransferase). The overarching Hypothesis for this current proposal is that decreased N-
sulfation of heparan sulfate proteoglycans and/or modification of the HS binding sites on matrix
protein ligands accelerates the development of diabetic nephropathy in individuals afflicted with
either type I or type II diabetes mellitus. To test this hypothesis we propose the following Specific Aims:
1.) To conduct in vivo studies on potential changes in either the rate of development or the degree of
progression of diabetic nephropathy in the kidneys of animal models in which NDST1 has been deleted in
glomerular podocytes; 2.)To explore the effects of hyperglycemia on podocyte-matrix interactions in vitro in
cells deficient for the enzyme NDST1.

## Key facts

- **NIH application ID:** 9952360
- **Project number:** 5R01DK111958-04
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** KEVIN John MCCARTHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $514,289
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952360

## Citation

> US National Institutes of Health, RePORTER application 9952360, The role ofglycosaminoglycan N-sulfation in glomerular biology/pathobiology (5R01DK111958-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952360. Licensed CC0.

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