Proximal tubular transport of Metallothionein-Mercury complexes and protection against nephrotoxicity.

Mercury (Hg) is an important environmental toxicant to which humans are exposed on a regular basis. Mercuric ions within biological systems do not exist as free ions. Rather, they are bound to free sulfhydryl groups (thiols) on biological molecules. Metallothionein (MT) is a cysteine-rich, metal-binding protein that has been shown to bind to heavy metals and reduce their toxic effects in target cells and organs. Little is known about the effect of MT on the handing and disposition of Hg. Therefore, the current study was designed to test the hypothesis that overexpression of MT alters the corporal disposition of Hg and reduces its nephrotoxicity. Furthermore, the current study examined the transport of Hg-MT complexes in isolated proximal tubules. Rats were treated with saline or Zn followed by injection with a non-nephrotoxic (0.5 µmol kg-1), moderately nephrotoxic (1.5 µmol kg-1), or significantly nephrotoxic (2.25 µmol kg-1) dose of HgCl2 (containing radioactive Hg). Pretreatment with Zn increased mRNA expression of MT and enhanced accumulation of Hg in the renal cortex of male and female rats. In addition, injection with Zn also protected animals from Hg-induced nephrotoxicity. Studies using isolated proximal tubules from rabbit kidney demonstrated that Hg-MT is taken up rapidly at the apical and basolateral membranes. The current findings suggest that at least part of this uptake occurs through an endocytic process. This study is the first to examine the uptake of Hg-MT complexes in isolated proximal tubules. Overall, the findings of this study suggest that supplementation with Zn may be a viable strategy for reducing the risk of Hg intoxication in at-risk populations.

Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As injured cells die and nephrons become sclerotic, remaining healthy nephrons attempt to compensate by undergoing various structural, molecular, and functional changes. While these changes are designed to maintain appropriate renal function, they may lead to additional cellular injury and progression of disease. As CKD progresses and filtration decreases, the ability to eliminate metabolic wastes and environmental toxicants declines. The inability to eliminate environmental toxicants such as arsenic, cadmium, and mercury may contribute to cellular injury and enhance the progression of CKD. The present review describes major molecular alterations that contribute to the pathogenesis of CKD and the effects of arsenic, cadmium, and mercury on the progression of CKD.

A refined chronology for the Middle and early Upper Paleolithic sequence of Riparo Mochi (Liguria, Italy).

The Riparo Mochi rock shelter, located on the Ligurian coast of Italy, is one of the most important early Upper Paleolithic sites on the Mediterranean rim. Its ∼10-m-deep stratigraphy comprises a Mousterian sequence, followed by various development stages of the Upper Paleolithic. A series of radiometric dates on marine shells bearing traces of human modification has provided a chronological framework for the final Mousterian and the Proto-Aurignacian of the site. Based on modeling results, the end of the Mousterian was dated between 44.0 and 41.8 ka cal BP (68% probability) and the beginning of the Proto-Aurignacian between 42.7 and 41.6 ka cal BP (68% probability). However, these estimates were based on a limited number of radiocarbon ages in the Mousterian levels. Here, we report new dating of the Mochi sequence using luminescence techniques, along with new radiocarbon measurements. The combination of these results using a Bayesian modeling approach allows for the first time the establishment of a more precise timing for the Mousterian occupation at the site. We show that Mousterian groups were already present at Riparo Mochi by at least 65 ka and continued to occupy the site for another 20 ka. The transition to the earliest Upper Paleolithic at the site is centered around 44.3-41.1 ka (95.4% probability), providing our best age estimate for the beginning of the Early Upper Paleolithic and the establishment of modern human groups in the Balzi Rossi. The sequence continues upward with a more evolved Aurignacian phase and a Gravettian phase starting at ∼26 ka or earlier.

Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis.

RATIONALE: Ineffective repair of a damaged alveolar epithelium has been postulated to cause pulmonary fibrosis. In support of this theory, epithelial cell abnormalities, including hyperplasia, apoptosis, and persistent denudation of the alveolar basement membrane, are found in the lungs of humans with idiopathic pulmonary fibrosis and in animal models of fibrotic lung disease. Furthermore, mutations in genes that affect regenerative capacity or that cause injury/apoptosis of type II alveolar epithelial cells have been identified in familial forms of pulmonary fibrosis. Although these findings are compelling, there are no studies that demonstrate a direct role for the alveolar epithelium or, more specifically, type II cells in the scarring process. OBJECTIVES: To determine if a targeted injury to type II cells would result in pulmonary fibrosis. METHODS: A transgenic mouse was generated to express the human diphtheria toxin receptor on type II alveolar epithelial cells. Diphtheria toxin was administered to these animals to specifically target the type II epithelium for injury. Lung fibrosis was assessed by histology and hydroxyproline measurement. MEASUREMENTS AND MAIN RESULTS: Transgenic mice treated with diphtheria toxin developed an approximately twofold increase in their lung hydroxyproline content on Days 21 and 28 after diphtheria toxin treatment. The fibrosis developed in conjunction with type II cell injury. Histological evaluation revealed diffuse collagen deposition with patchy areas of more confluent scarring and associated alveolar contraction. CONCLUSIONS: The development of lung fibrosis in the setting of type II cell injury in our model provides evidence for a causal link between the epithelial defects seen in idiopathic pulmonary fibrosis and the corresponding areas of scarring.