We are interested in how heavy metals interact with biological systems to cause toxicity. Our central project focuses on the heavy metal cadmium and its effects in the kidney. Humans are commonly exposed to cadmium through contaminated food stuff and/or through smoking. The heavy metal has the highest accumulation potential in the renal proximal tubule cells in comparison at all tissues of the human body where the metal exhibits and overall half-life of 30 years. We are investigating how this leads to demise of tubular functioning, inflammation, fibrosis and eventually contributes to chronic kidney disease. We primarily use in vitro cell models consisting of either human proximal tubule cells isolated from human kidney or immortalized proximal tubule cells transfected with various genes thought to contribute to handling of this metal. We are currently assessing the role of stem cells in these models and how they contribute to regeneration of the proximal tubule. We are also studying how high glucose concentrations seen in diabetes can contribute to toxic responses of the kidney and lead to a progression to end-stage renal disease.
One molecule that we have focused on in the past is the protein primarily responsible for sequestration of cadmium, metallothionein. We have characterized this gene family in the renal system and discovered that a unique isoform of this gene family, metallothionein-3, contributes to the maintenance of epithelial morphology and can counter the mesenchymal-to-epithelial transition that can occur in some toxic responses.
Through collaborations with other members in the department, we also study how cadmium and arsenic lead to the formation of bladder cancer.
- Sens DA, Cisek KL, Garrett SH, Somji S, Dunlevy JR, Sens MA, Conway P, Doze VA. STEERing an IDeA in Undergraduate Research at a Rural Research Intensive University. Acad Pathol. 2017 Oct 13;4:2374289517735092. doi: 10.1177/2374289517735092. eCollection 2017 Jan-Dec.
- Shrestha S, Somji S, Sens DA, Slusser-Nore A, Patel DH, Savage E, Garrett SH. Human renal tubular cells contain CD24/CD133 progenitor cell populations: Implications for tubular regeneration after toxicant induced damage using cadmium as a model. Toxicol Appl Pharmacol. 2017 Sep 15;331:116-129. doi: 10.1016/j.taap.2017.05.038. Epub 2017 Jun 3.
- Voels B, Wang L, Sens DA, Garrett SH, Zhang K, Somji S. The unique C- and N-terminal sequences of Metallothionein isoform 3 mediate growth inhibition and Vectorial active transport in MCF-7 cells. BMC Cancer. 2017 May 25;17(1):369. doi: 10.1186/s12885-017-3355-9.
- Slusser-Nore A, Garrett SH, Zhou XD, Sens DA, Sens MA, Somji S. The expression of keratin 6 is regulated by the activation of the ERK1/2 pathway in arsenite transformed human urothelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:41-53. doi: 10.1016/j.taap.2017.05.007. Epub 2017 May 10.
- Zhang R, Wang L, Garrett SH, Sens DA, Dunlevy JR, Zhou ZD, Somji S. Elevated connexin 43 expression in arsenite-and cadmium-transformed human bladder cancer cells, tumor transplants and selected high grade human bladder cancer. Exp Toxicol Pathol 68(9): 479-491, 2016.
- Sandquist EJ, Somji S, Dunlevy JR, Garrett SH, Zhou XD, Slusser-Nore A, Sens DA. Loss of N-Cadherin Expression in Tumor Transplants Produced From As+3- and Cd+2-Transformed Human Urothelial (UROtsa) Cell Lines. PLoS One. 11(5): e156310, 2016
- Slusser, A, Larson, J, Zang, R, Zhou, XD, Somji S, Garrett SH, Sens, DA, Dunlevy JR. SPARC Expression is Selectively Suppressed in Tumor Initiating Urospheres Isolated from As+3-and Cd+2-Transformed Human Urothelial Cells (UROtsa) Stably Transfected with SPARC. PLoS One. 11(1): e0147362, 2016
- Slusser A, Bathula CS, Sens DA, Somji S, Sens MA, Zhou XD, Garrett, SH. Cadherin Expression, Vectorial Active Transport, and Metallothionein Isoform 3 Mediated EMT/MET Responses in Cultured Primary and Immortalized Human Proximal Tubule Cells. Plos One. 10(3):e0120132, 2015
- Slusser A, Zheng Y, Zhou XD, Somji S, Sens DA, Sens MA, Garrett SH. Metallothionein isoform 3 expression in human skin, related cancers and human skin derived cell cultures. Toxicol Lett, 232(1):141-148, 2014
- Mehus AA, Muhonen WW, Garrett SH, Somji S, Sens DA, Shabb JB. Quantitation of Human Metallothionein isoforms: A family of small highly conserved cysteine-rich proteins. Mol Cell Proteomics. 13(4):1020-1033, 2014
Complete List of Publications