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ORIGINAL ARTICLE

Induction of Metallothionein-I Protects Glomeruli from Superoxide-Mediated Increase in Albumin Permeability

Ram Sharma^*, Mukut Sharma^*,1, Prasun K. Datta and Virginia J. Savin^*

^* Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Wisconsin 53226 and
Department of Medicine, Division of Nephrology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901

Metallothioneins (MT) are low-molecular-weight, heat-stable, cysteine-rich proteins with four isoforms. MT-I and MT-II are ubiquitous and are induced by oxidative, physical, and chemical stress. MT-I is an efficient scavenger of superoxide (^•O₂) and hydroxyl ion (OH^-). We have demonstrated that ^•O₂ and hypohalous acid can cause an increase in glomerular albumin permeability (P_alb) in vitro. The purpose of this study was to document the protective effect of MT gene product on the ^•O₂-mediated increase in P_alb. Glomeruli from Sprague-Dawley rats in 4% BSA medium were incubated for 4 hr at 37°C in duplicate tubes. Each set contained glomeruli alone or with 5 µM Cd⁺⁺, 0.3 mM Spermine-NONOate (NO donor), 0.3 mM Sulfo-NONOate (nitrous oxide donor), 0.6 mM SNP (nonspecific NO donor) and SNP + carboxy-PTIO (10 mg/ml). After incubation, one set of tubes was used to isolate total RNA for the measurement of the mRNA levels of MT-I by reverse transcriptase polymerase chain reaction (RT-PCR). Duplicate tubes were incubated for an additional 10 min with 10 nM of ^•O₂, and P_alb was measured using video microscopy. RT-PCR of total RNA from Cd⁺⁺ and Spermine-NONOate treated glomeruli revealed a 2-fold induction of MT-I expression at the mRNA level.^•O₂ caused a significant increase in P_alb (0.8 ± 0.06 vs. control 0.0 ± 0.12, P < 0.05) and induction of MT-I in glomeruli by Cd⁺⁺ or by Spermine-NONOate blocked this effect (0.21 ± 0.12 and 0.24 ± 0.19, respectively, P < 0.05 vs. ^•O₂). In contrast, Sulfo-NONOate and SNP did not induce mRNA for MT-I in glomeruli and did not provide protection against ^•O₂-mediated increase in P_alb. We conclude that MT-I gene products may play an important role in protecting the glomerular filtration barrier from the injury induced by reactive oxygen species in immune and/or nonimmune renal diseases.

Key Words: metallothioneins • glomerular albumin permeability • reactive oxygen species

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