Thursday, November 21, 2024
11/21/2024
Project Summary Approximately 30 million adults in the United States suffer with chronic kidney disease (CKD), which is characterized by a progressive loss of functional renal mass and subsequent compensatory changes, such as increased renal plasma flow, increased single nephron glomerular filtration rate, and renal cellular hypertrophy. This hypertrophy is particularly striking in proximal tubular cells. Owing to the enhanced plasma flow and filtration rate of functioning nephrons, proximal tubular cells of these nephrons may be exposed to higher levels of xenobiotics, metabolic wastes, and nephrotoxicants. Consequently, these substances may be taken up more readily by hypertrophied proximal tubular cells. The increased exposure to, and probable uptake of, xenobiotics, wastes, and nephrotoxicants likely enhances the risk of hypertrophied proximal tubular cells being affected adversely by these substances. One nephrotoxicant of particular concern is mercury (Hg). One of the most common forms of Hg is inorganic mercury (Hg2+). Exposure to Hg2+ can lead to serious, detrimental effects in proximal tubular cells and has been shown to exacerbate the progression of CKD. Our preliminary data show that the remnant kidney of nephrectomized rats accumulates more Hg2+ than a single kidney of non- nephrectomized rats. Furthermore, the uptake of Hg2+ at the luminal membrane of proximal tubular cells is enhanced in hypertrophied tubules. However, the basolateral uptake of Hg in hypertrophied proximal tubular cells has not been characterized fully. Based on our preliminary data, we hypothesize that cellular hypertrophy is associated with an increase in the basolateral transport of Hg2+ into proximal tubular cells. Uptake of Hg2+ at the basolateral membrane of proximal tubular cells appears to involve organic anion transporters, OAT1 and OAT3, and at least one other unidentified transporter. Prior to assessing the effects of compensatory hypertrophy on the basolateral uptake of mercuric conjugates, we will seek to identify additional carriers that are involved in the basolateral uptake of Hg under normal conditions. Therefore, we propose 1) To determine if the basolateral uptake of cysteine-S-conjugates of Hg2+ into normal proximal tubular cells is mediated, in part, by LAT4, y+LAT1 and/or OCT2. Once we have a more complete understanding of the basolateral mechanisms that mediate the uptake of Hg under normal conditions, we will 2) determine if the basolateral uptake of Cys-S-conjugates of Hg2+ into proximal tubular cells increases following compensatory cellular hypertrophy. Finally, we will 3) identify the specific intracellular events that lead to cellular intoxication following exposure to Hg and to determine if hypertrophied cells are more susceptible to these events. Given the incidence of CKD and the prevalence of toxicants in our environment, it is important to human health that we have a thorough understanding of the way in which mercuric ions and other relevant nephrotoxicants are handled by the kidney. The findings of the proposed studies will not only be significant clinically, but they will also make significant contributions to the field of Hg toxicology.
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