Limits...
Nephroprotective effect of heparanase in experimental nephrotic syndrome.

Assady S, Alter J, Axelman E, Zohar Y, Sabo E, Litvak M, Kaplan M, Ilan N, Vlodavsky I, Abassi Z - PLoS ONE (2015)

Bottom Line: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes.Albuminuria was investigated at days 0, 7, and 14 thereafter.Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.

ABSTRACT

Background: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model.

Methods: BALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity.

Results: ADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice.

Conclusions: Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.

No MeSH data available.


Related in: MedlinePlus

Adriamycin causes renal damage in wild type mice but not in hpa-TG mice.wt or hpa-TG mice were injected with Adriamycin (ADR) or served as control (sham). Two weeks post injection, the animals were sacrificed. Representative images of H&E (A) and Masson’s trichrome (B) staining of paraffin-embedded kidney sections from various experimental groups (scale bar = 100 μm). n = 6 mice per each experimental group, from three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4364762&req=5

pone.0119610.g003: Adriamycin causes renal damage in wild type mice but not in hpa-TG mice.wt or hpa-TG mice were injected with Adriamycin (ADR) or served as control (sham). Two weeks post injection, the animals were sacrificed. Representative images of H&E (A) and Masson’s trichrome (B) staining of paraffin-embedded kidney sections from various experimental groups (scale bar = 100 μm). n = 6 mice per each experimental group, from three independent experiments.

Mentions: When blindly observed by light microscopy, H&E and PAS stained cross sections of paraffin-embedded hpa-TG kidneys, both Adriamycin-injected and sham animals, could not be distinguished from those obtained from healthy BALB/c mice. The glomerular capillary loops were open, and tubulointerstitial structure appeared normal. Conversely, cross sections from Adriamycin-injected wild type mice showed variable degrees of glomerular and tubular damage (mild to severe), as evident by the presence of a proteinatious material inside the urinary space and tubular lumen, as well as tubular atrophy and dilation (Fig. 3A). However, two weeks following Adriamycin-induced injury, no signs of interstitial fibrosis were detected by Masson’s trichrome staining (Fig. 3B).


Nephroprotective effect of heparanase in experimental nephrotic syndrome.

Assady S, Alter J, Axelman E, Zohar Y, Sabo E, Litvak M, Kaplan M, Ilan N, Vlodavsky I, Abassi Z - PLoS ONE (2015)

Adriamycin causes renal damage in wild type mice but not in hpa-TG mice.wt or hpa-TG mice were injected with Adriamycin (ADR) or served as control (sham). Two weeks post injection, the animals were sacrificed. Representative images of H&E (A) and Masson’s trichrome (B) staining of paraffin-embedded kidney sections from various experimental groups (scale bar = 100 μm). n = 6 mice per each experimental group, from three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4364762&req=5

pone.0119610.g003: Adriamycin causes renal damage in wild type mice but not in hpa-TG mice.wt or hpa-TG mice were injected with Adriamycin (ADR) or served as control (sham). Two weeks post injection, the animals were sacrificed. Representative images of H&E (A) and Masson’s trichrome (B) staining of paraffin-embedded kidney sections from various experimental groups (scale bar = 100 μm). n = 6 mice per each experimental group, from three independent experiments.
Mentions: When blindly observed by light microscopy, H&E and PAS stained cross sections of paraffin-embedded hpa-TG kidneys, both Adriamycin-injected and sham animals, could not be distinguished from those obtained from healthy BALB/c mice. The glomerular capillary loops were open, and tubulointerstitial structure appeared normal. Conversely, cross sections from Adriamycin-injected wild type mice showed variable degrees of glomerular and tubular damage (mild to severe), as evident by the presence of a proteinatious material inside the urinary space and tubular lumen, as well as tubular atrophy and dilation (Fig. 3A). However, two weeks following Adriamycin-induced injury, no signs of interstitial fibrosis were detected by Masson’s trichrome staining (Fig. 3B).

Bottom Line: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes.Albuminuria was investigated at days 0, 7, and 14 thereafter.Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.

ABSTRACT

Background: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model.

Methods: BALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity.

Results: ADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice.

Conclusions: Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.

No MeSH data available.


Related in: MedlinePlus