Research
The research focus areas in the Moeckel lab are centered on the vascular and cellular biology of acute kidney injury and progression of chronic kidney disease:
- Cell survival mechanisms under hypertonic conditions: the focus is on COX2-dependent survival of renal medullary cells and the role of chaperones such as organic osmolytes and heat shock proteins in preventing apoptosis.
- The role of hyperphosphatemia in progression of chronic kidney disease (CKD): phosphate-induced AKI and progression of interstitial fibrosis and the molecular mechanisms thereof.
- Cell-matrix interaction and its role in cell volume regulation: cytoplasmic membrane and cytoskeleton proteins stimulate signaling pathways that regulate osmo-adaptive responses and cell volume.
- The role of renal fibroblasts in progression of diabetic nephropathy: we examine the molecular mechanisms how high glucose stimulates collagen and fibronectin synthesis in cortical and medullary fibroblasts.
Hyperosmotic stress is highly prevalent in the kidney medulla and how cells survive in this lethal environment is largely unknown. Medullary interstitial cells contain very high concentrations of cyclooxygenase 2 (COX2) that synthesizes the prostanoids PGE2 and PGI2, which are important in mediating cell survival under hyperosmotic conditions. Our lab discovered that COX2 activity is an important regulator of the compatible osmolyte response in medullary kidney cells and that Integrins play an important role in the cell-matrix interaction that leads to accumulation of compatible osmolytes and cell volume regulation. The mechanisms employed by kidney cells to sense the hypertonic environment and communicate this signal to transcription factors such as TonEBP/NFAT5, which subsequently drive the expression of osmolyte transporters and heat shock proteins, is one focus of our studies.
Renal fibroblasts play an important role in the development of interstitial fibrosis and progression of CKD. Our lab is currently investigating the mechanisms that lead to increased synthesis of fibrogenic molecules such as fibronectin and collagen in renal fibroblasts under hyperphosphatemic and hyperglycemic conditions. We have generated primary and immortalized fibroblast cell lines from renal cortex and medulla, which we employ to study signaling pathways and the regulation of transcription factors that drive progression of fibrosis. Moreover, we are investigating the role of endothelial cell injury in progression of renal fibrosis using diabetic mouse models.
Students and post-docs in my lab are exposed to wide variety of physiologic, biochemical, cell biological, molecular and cell and tissue organ culture techniques as well as several animal models utilizing transgenic and knock-out technologies. Moreover, the student will be exposed to human kidney biopsy material in an attempt to correlate findings in the animal and cell culture models with actual patient kidney pathology.
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People
Current members of the Moeckel laboratory:
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Gilbert W. Moeckel, MD, PhD, FASNAssociate Professor of Pathology Director of Renal Pathology and Electron Microscopy Laboratory |
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Dong Chen, MD
Dong is working on elucidating the mechanisms of hypertonicity-induced apoptosis. He is currently examining the mechanisms that lead to efflux of pro-apoptotic molecules from the mitochondrial inter-membrane space to the cytoplasm following exposure of cells to a hyperosmotic environment. He is further examining the signaling pathways involved in hypertonicity-induced activation of mitochondrial apoptotic pathways. |
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Zhonghai Chen, PhD Zhonghai is examining the mechanisms of phosphate-induced AKI and how this contributes to progression of CKD. He is using in vivo animal models of CKD and hyperphosphatemia to investigate the role of phosphate in progression of renal fibrosis. Moreover, he is studying the role of phosphate on intracellular calcium signaling.
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Publications
Selected Publications:
Gilbert W. Moeckel, Li Zhang, Chuan-Ming Hao, Agnes B. Fogo, Ambra Pozzi and Matthew D. Breyer. COX2 activity promotes organic osmolyte accumulation adaptation of renal medullary interstitial cells from hypertonic stress. J Biol Chem 278(21):19352-19357, 2003.
GW Moeckel, L Zhang, X Chen, M Rossini, R Zent and A Pozzi. Role of integrin α1ß1 in the regulation of renal medullary osmolyte concentration. Am J Physiol,2006, 290:F223-31.
Gilbert W. Moeckel, Ramin Shadman, Joy M. Fogel and Sayed M.H. Sadrzadeh. Organic osmolytes betaine, sorbitol and inositol are potent inhibitors of erythrocyte membrane ATPases. Life Sciences 71(20):2413-2424, 2002.
Gilbert W. Moeckel, Li-Wen Lai, Walter G. Guder, H. Moo Kwon and Yeong-Hau H. Lien. Kinetics and osmoregulation of Na and Cl-dependent betaine transporter in rat renal medulla. American Journal of Physiology 272(Renal Physiol. 41):F100-F106, 1997.
Gilbert W. Moeckel and Yeong-Hau H. Lien. Distribution of de novo synthesized betaine in rat kidney: role of renal synthesis on medullary betaine accumulation. American Journal of Physiology 272(Renal Physiol. 41):F94-F99. 1997.
Gilbert W. Moeckel, Jürgen Hallbach and Walter G. Guder. Purification of human and rat kidney aldose reductase. Enzyme Protein 48:45-50, 1994-95.
Gilbert W. Moeckel and Yeong Hau H. Lien. Bicarbonate dependency of betaine synthesis in cultured LLC‑PKI cells. American Journal of Physiology 266:F512-F515, 1994.
Stefan Pummer, William H. Danzler, Yeong-Hau H. Lien, Gilbert W. Moeckel, Katharina Völker and Stefan Silbernagl. Reabsorption of betaine in Henle’s loops of rat kidney in vivo. American Journal of Physiology 278:F434-F439, 2000.
S.T. Lamitina, K. Baman, R. Morrison, G. W. Moeckel and K. Strange. Adaptation of the nematode C. elegans to extreme osmotic stress. Am J Physiol, Cell Physiol, 2004:286:C785-91.
Kwon M, Na K, Moeckel G, Lee S, and Kwon HM. Urea promotes TonEBP expression and celllar adaptation in extreme hypertonicity. Pflugers Archive-European Journal of Physiology, 2009, in press.
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