Presence of heparan sulfate in the glomerular basement membrane

Kanwar, Yashpal S.; Farquhar, Marilyn G.

doi:10.1073/pnas.76.3.1303

Cited by 494 publications

(204 citation statements)

References 29 publications

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…HS is a major constituent of the GBM and is responsible for its negative charge (15). HS is known to disassemble nucleic acid-containing, cationic polymer polyplexes (20).…”

Section: Nanoparticle Components Remain Assembled In Vivo and Willmentioning

confidence: 99%

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Zuckerman

Choi²,

Han³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

318

269

View full text Add to dashboard Cite

Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier-the glomerular basement membrane (GBM)-can disassemble cationic cyclodextrin-containing polymer (CDP)-based siRNA nanoparticles and, thereby, facilitate their rapid elimination from circulation. Using confocal and electron microscopies, positron emission tomography, and compartment modeling, we demonstrate that siRNA nanoparticles, but not free siRNA, accumulate and disassemble in the GBM. We also confirm that the siRNA nanoparticles do not disassemble in blood plasma in vitro and in vivo. This clearance mechanism may affect any nanoparticles that assemble primarily by electrostatic interactions between cationic delivery components and anionic nucleic acids (or other therapeutic entities). pharmacokinetics | glomerulusA major challenge with the use of small interfering RNA (siRNA) in mammals is their delivery to intracellular locations in specific tissues (1). The two most investigated approaches to siRNA delivery involve the combination of siRNA with cationic lipids (lipoplexes, liposomes, micelles) or cationic polymers (polyplexes) (2). Polymer-based siRNA delivery vehicles can be tuned to be nonimmunogenic, nononcogenic, nontoxic, and targeted (3). A targeted nanoparticle formulation of siRNA (not chemically modified) with a cationic, cyclodextrin-containing polymer (CDP)-based delivery vehicle (clinical version denoted CALAA-01) was shown to accumulate in human tumors and deliver functional siRNA from a systemic, i.v. infusion (4). This first-in-human study demonstrated the clinical potential for cationic polymerbased siRNA delivery systems.Like most cationic polymer-based siRNA delivery systems (5-9), the siRNA/CDP nanoparticle is rapidly eliminated from circulation (shown in mice, monkeys, and humans) (10-12). In fact, polymer complexation often does not extend the circulation time of siRNA. The rapid clearance of these siRNA nanoparticles is puzzling because they are engineered to be above the size cutoff for single-pass clearance via renal filtration (13). In understanding the mechanism behind the rapid clearance of this type of cancer therapeutic, we can efficiently seek ways to increase their circulation time and, thus, enhance their anticancer efficacy (3).We hypothesize that the paradoxical renal clearance of polycation-nucleic acid nanoparticles results from their binding and disassembly by components of the renal filtration barrier. Three key properties of such nanoparticles (diameters between 10 and 100 nm, positive zeta potentials, and electrostatically driven selfassembly) make them susceptible to this mechanism of clearance.The renal filtration barrier, located within the glomerulus of the nephron, consists of three layers that must be traversed to enter the urinary space. These three layers are the glomerular endothelial fenestrations (≈100 n...

show abstract

“…HS is a major constituent of the GBM and is responsible for its negative charge (15). HS is known to disassemble nucleic acid-containing, cationic polymer polyplexes (20).…”

Section: Nanoparticle Components Remain Assembled In Vivo and Willmentioning

confidence: 99%

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Zuckerman

Choi²,

Han³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

318

269

View full text Add to dashboard Cite

show abstract

“…The negative charge of the filtration barrier depends on the presence of glycoconjugates in both the podocyte coat (Kerjaschki et al, 1984;Dekan et al, 1991) and the GBM (Kanwar and Farquhar, 1979;Kanwar et al, 1980). Glycoconjugates also appear to be involved in the maintenance of the podocyte morphology (Andrews, 1979).…”

mentioning

confidence: 99%

Renal corpuscle of the sturgeon kidney: An ultrastructural, chemical dissection, and lectin‐binding study

2003

View full text Add to dashboard Cite

The sturgeon is an ancient species of fish that thrives in a wide range of ecological environments, from freshwater to seawater. Basic in this process of adaptation is the ability of the kidney to control fluid filtration and urine formation. However, the morphological basis of this process is mostly unknown. The aim of the present study was to use microdissection techniques (scanning electron microscopy (SEM), transmission electron microscopy (TEM), and lectin-binding histochemistry) to examine the structure of the renal corpuscle of the sturgeon Acipenser nacarii in order to reveal morphologic features that could be related to function, phylogeny, and habitat. The renal corpuscles are aligned along the intrarrenal arteries. The urinary pole shows a siphon-like neck segment (NS) in 92% of the nephrons, whose structural characteristics are different from those of other fish. The podocytes have cuboidal cellular bodies, intercellular contacts, and poorly developed cell processes. The podocyte glycocalyx contains N-acetylglucosamine and lacks sialic acid. The structural and lectin-binding patterns are similar to those found in the immature mammalian kidney. The glomerular basement membrane (GBM) is very thick and consists of three layers: a lamina rara externa, a lamina densa, and a thick subendothelial lamina. The latter contains tubular microfibrils, collagen fibers, and long mesangial cell processes. Frequently, the podocyte bodies attach directly to the GBM, and the area occupied by the filtration slits is very small. Furthermore, the GBM shows a glycosylation pattern different from that observed in most vertebrates. Contrary to what would be expected in sturgeons living in freshwater, the A. nacarii renal corpuscle morphology suggests a low glomerular filtration rate. Anat Rec Part A 272A: 563-573, 2003.

show abstract

“…2 While the former may be a function of packing of the collagen polypeptide chains, recent studies suggest that the latter may reside in a heparan sulfate glycosaminoglycan 3 that has been isolated, characterized, and shown to be an integral constituent of the basement membrane.…”

mentioning

confidence: 99%

Effect of Diabetes on the Glycosaminoglycan Component of the Human Glomerular Basement Membrane

1982

View full text Add to dashboard Cite

SUMMARYThe glycosaminoglycan (heparan sulfate) component of glomerular basement membranes from human kidneys of diabetic and nondiabetic subjects has been quantitated after isolation from protease digests of the membranes on OEAE-cellulose microcolumns. A significant decrease (P < 0.005) in the glycosaminoglycan content of diabetic membranes was observed. Heparan sulfate was identified as the predominant glycosaminoglycan in both diabetic and control subjects and the extent of its sulfation appeared to be similar. The reduced level of glycosaminoglycan in the diabetic glomerular basement membrane was accompanied by a significant elevation of hexoses, which are primarily associated with the collagen component, suggesting that a redistribution of basement membrane macromolecules occurs in the diabetic state. Since heparan sulfate has been implicated as a major component of the glomerular anionic filtration barrier, its decreased content in diabetic basement membranes may contribute to the proteinuria observed in this disease. DIABETES 37:738-741, August 1982.A lthough it has been recognized for some time that basement membrane thickening and mesangial expansion is a characteristic morphologic feature of diabetic glomerulopathy, the relationship between these ultrastructural alterations and the clinically observed proteinuria remains to be established. 1 As the major functional component of the renal glomerulus and the only continuous anatomic barrier between the blood and urine, the basement membrane would appear to be a logical site at which changes brought about by disease could lead to a filtration defect.The primary factors determining glomerular basement membrane permeability appear to be pore size as well as fixed electrostatic charge.2 While the former may be a function of packing of the collagen polypeptide chains, recent studies suggest that the latter may reside in a heparan sulfate glycosaminoglycan 3 that has been isolated, characterized, and shown to be an integral constituent of the basement membrane. 4>sSince the glycosaminoglycan component was until lately unrecognized and is present in very small amounts 6 ( < 1 % by weight), previous studies of diabetic basement membranes have not provided information on this component.In the present investigation we have quantitated the heparan sulfate of glomerular basement membranes from human diabetics with the help of a recently developed DEAE-cellulose microcolumn fractionation procedure 6 and find that it is present in significantly decreased amounts. MATERIALS AND METHODSHuman kidneys from diabetic and nondiabetic subjects were obtained at autopsy from the New England Deaconess and the Brigham and Women's Hospitals and stored at -70°C in airtight plastic bags until use. Glomerular basement membranes from individual kidneys were studied from 9 diabetic and 10 nondiabetic subjects, whose ages ranged from 43 to 66 yr (mean 60 yr) and from 37 to 68 yr (mean 59 yr), respectively. In both groups all individuals but one were above the age of 50. In the diabetics...

show abstract

Presence of heparan sulfate in the glomerular basement membrane

Cited by 494 publications

References 29 publications

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Renal corpuscle of the sturgeon kidney: An ultrastructural, chemical dissection, and lectin‐binding study

Effect of Diabetes on the Glycosaminoglycan Component of the Human Glomerular Basement Membrane

Contact Info

Product

Resources

About