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4. List of Contributors

Author

Abramovitz, Blaise, primary, Adu, Dwomoa, additional, Afshinnia, Farsad, additional, Agarwal, Anupam, additional, Andrews, Sarah C., additional, Appel, Gerald, additional, Bailey, James L., additional, Bakris, George L., additional, Bauer, Carolyn A., additional, Baxi, Pravir V., additional, Berns, Jeffrey S., additional, Birks, Peter, additional, Bomback, Andrew, additional, Bose, Anirban, additional, Brosius, Frank C., additional, Brown, Lee K., additional, Bushinsky, David A., additional, Busse, Laurence W., additional, Campbell, Ruth C., additional, Canney, Mark, additional, Cathro, Helen, additional, Chávez-Iñiguez, Jonathan, additional, Chawla, Lakhmir S., additional, Chen, Sheldon, additional, Chertow, Glenn M., additional, Chew, Emily Y., additional, Chonchol, Michel, additional, Clegg, Deborah J., additional, Clive, David M., additional, Clive, Pia H., additional, Cohen, Scott D., additional, Collins, Ashte' K., additional, Cooper, James E., additional, Correa-Rotter, Ricardo, additional, Cukor, Daniel, additional, Dalal, Monica, additional, Davenport, Andrew, additional, Davis, Scott, additional, Davison, Sara N., additional, Delanaye, Pierre, additional, de Zeeuw, Dick, additional, Dobre, Mirela A., additional, Drawz, Paul, additional, Ebert, Natalie, additional, Eggers, Paul, additional, Ferrè, Silvia, additional, Freedman, Barry I., additional, Furth, Susan L., additional, Gao, Bixia, additional, García-García, Guillermo, additional, Gashti, Casey N., additional, Germino, Gregory G., additional, Goldsmith, David, additional, Golestaneh, Ladan, additional, Goligorsky, Michael S., additional, Greenberg, Arthur, additional, Gregg, L. Parker, additional, Guay-Woodford, Lisa M., additional, Hamm, Lee, additional, Hart, Allyson, additional, Haselby, Danielle, additional, Hedayati, S. Susan, additional, Heerspink, Hiddo J.L., additional, Herzog, Charles A., additional, Hostetter, Thomas H., additional, House, Andrew A., additional, Hruska, Keith A., additional, Ishani, Areef, additional, Isom, Robert T., additional, James, Matthew T., additional, Jhaveri, Kenar D., additional, Johansen, Kirsten, additional, Johnson, Richard J., additional, Kang, Duk-Hee, additional, Kanno, Hiroko, additional, Kanno, Yoshihiko, additional, Karambelkar, Amrita D., additional, Karet Frankl, Fiona E., additional, Khoury, Charbel C., additional, Kimmel, Paul L., additional, Kopp, Jeffrey B., additional, Korbet, Stephen M., additional, Kruzel-Davila, Etty, additional, Kummer, Andrew, additional, LaFave, Laura, additional, Lakkis, Jay I., additional, Lerman, Lilach O., additional, Levin, Adeera, additional, Lew, Susie Q., additional, Luyckx, Valerie A., additional, Mattoo, Tej K., additional, Maynard, Sharon E., additional, McCullough, Peter A., additional, Mehrotra, Rajnish, additional, Meyer, Timothy W., additional, Mitch, William E., additional, Moe, Orson W., additional, Mohandes, Samer, additional, Moss, Alvin H., additional, Moxey-Mims, Marva, additional, Murugapandian, Sangeetha, additional, Nath, Karl A., additional, Neugarten, Joel, additional, Neyra, Javier A., additional, Nissenson, Allen R., additional, Nobakht, Ehsan, additional, Nolin, Thomas D., additional, Norris, Keith C., additional, Norton, Jenna M., additional, Nowak, Kristen L., additional, Ojo, Akinlolu O., additional, Pahl, Madeleine V., additional, Paller, Mark S., additional, Palmer, Biff F., additional, Palmer, Nicholette D., additional, Patel, Samir S., additional, Pecoits-Filho, Roberto, additional, Peitzman, Steven J., additional, Peixoto, Aldo J., additional, Pham, Phuong-Thu T., additional, Pham, Phuong-Chi T., additional, Piraino, Beth, additional, Pisoni, Roberto, additional, Rabelink, Ton, additional, Radhakrishnan, Jai, additional, Rahman, Mahboob, additional, Raj, Dominic S., additional, Ramírez-Sandoval, Juan C., additional, Rangaswami, Janani, additional, Reckelhoff, Jane F., additional, Regunathan-Shenk, Renu, additional, Reule, Scott, additional, Ronco, Claudio, additional, Rosenberg, Mark E., additional, Rosner, Mitchell H., additional, Rovin, Brad, additional, Roy-Chaudhury, Prabir, additional, Ruebner, Rebecca, additional, Rule, Andrew D., additional, Sands, Jeff M., additional, Schlanger, Lynn E., additional, Schrauben, Sarah J., additional, Seliger, Stephen, additional, Shah, Maulin, additional, Sterns, Richard H., additional, Stites, Erik, additional, Sugatani, Toshifumi, additional, Textor, Stephen C., additional, Thadhani, Ravi, additional, Thajudeen, Bijin, additional, Thakar, Surabhi, additional, Thomas, George, additional, Townsend, Raymond R., additional, Turner, Jeffrey, additional, Unruh, Mark L., additional, Urquhart, Bradley L., additional, Vassalotti, Joseph A., additional, Vaziri, Nosratola D., additional, Velasquez, Manuel T., additional, Ver Halen, Nisha, additional, Waddy, Salina P., additional, Wang, Jinwei, additional, Weber, Marc, additional, Weir, Matthew R., additional, White, Christine A., additional, Whittier, William L., additional, Williams, Matthew J., additional, Wiseman, Alexander C., additional, Wymer, David C., additional, Wymer, David T.G., additional, Yee, Jerry, additional, Zhang, Luxia, additional, Zhuang, Shougang, additional, and Ziyadeh, Fuad N., additional

Published
2020
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5. Nephrogenic Calciphylaxis Arising after Bariatric Surgery: A Case Series.

Author

Xia, Joyce, Tan, Alice J., Biglione, Bianca, Cucka, Bethany, Ko, Lauren, Nguyen, Emily D., Khoury, Charbel C., Robinson, Malcolm K., Nigwekar, Sagar U., and Kroshinsky, Daniela

Subjects
BARIATRIC surgery, HYPERPHOSPHATEMIA, VITAMIN D deficiency, VITAMIN K, VITAMIN deficiency, DIETARY supplements, CALCIPHYLAXIS
Abstract

Nephrogenic calciphylaxis is associated with multiple risk factors including long-term dialysis dependence, hyperphosphatemia, hypercalcemia, parathyroid hormone derangements, vitamin K deficiency, obesity, diabetes mellitus, warfarin use, and female sex. Bariatric surgery is known to cause altered absorption, leading to mineral and hormonal abnormalities in addition to nutritional deficiency. Prior case reports on calciphylaxis development following bariatric surgery have been published, though are limited in number. We report a case series of five bariatric patients from a single institution who developed nephrogenic calciphylaxis between 2012 and 2018. These patients had a history of bariatric surgery, and at the time of calciphylaxis diagnosis, demonstrated laboratory abnormalities associated with surgery including hypercalcemia (n = 3), hyperparathyroidism (n = 2), hypoalbuminemia (n = 5), and vitamin D deficiency (n = 5), in addition to other medication exposures such as vitamin D supplementation (n = 2), calcium supplementation (n = 4), warfarin (n = 2), and intravenous iron (n = 1). Despite the multifactorial etiology of calciphylaxis and the many risk factors present in the subjects of this case series, we submit that bariatric surgery represents an additional potential risk factor for calciphylaxis directly stemming from the adverse impact of malabsorption and overuse of therapeutic supplementation. We draw attention to this phenomenon to encourage early consideration of calciphylaxis in the differential for painful skin lesions arising after bariatric surgery as swift intervention is essential for these high-risk patients. [ABSTRACT FROM AUTHOR]

Published
2024
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6. De novo NAD+ biosynthetic impairment in acute kidney injury in humans

Author

Poyan Mehr, Ali, Tran, Mei T., Ralto, Kenneth M., Leaf, David E., Washco, Vaughan, Messmer, Joseph, Lerner, Adam, Kher, Ajay, Kim, Steven H., Khoury, Charbel C., Herzig, Shoshana J., Trovato, Mary E., Simon-Tillaux, Noemie, Lynch, Matthew R., Thadhani, Ravi I., Clish, Clary B., Khabbaz, Kamal R., Rhee, Eugene P., Waikar, Sushrut S., Berg, Anders H., and Parikh, Samir M.

Published
2018
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9. Contributors

Author

Agarwal, Rajiv, primary, Alfaadhel, Talal, additional, Andersen, Martin J., additional, Asplin, John Robert, additional, Avasare, Rupali S., additional, Bakris, George L., additional, Bansal, Amar D., additional, Baxi, Pravir V., additional, Berkoben, Michael, additional, Bieber, Scott D., additional, Buchkremer, Florian, additional, Burgner, Anna Marie, additional, Byrd, James Brian, additional, Cattran, Daniel, additional, Choudhury, Devasmita, additional, Granado, Rolando Claure-Del, additional, Denker, Bradley M., additional, Derebail, Vimal K., additional, Desnick, Robert J., additional, Lullo, Luca di, additional, Duronville, John V., additional, Eknoyan, Garabed, additional, Kateb, Mina El, additional, Elliott, William J., additional, Ennis, Jennifer L., additional, Fervenza, Fernando C., additional, Figlin, Robert A., additional, Galvin, Zita, additional, Garimella, Pranav S., additional, Gipson, Debbie S., additional, Gipson, Patrick E., additional, Goldfarb, David S., additional, Greenberg, Arthur, additional, Haller, Hermann, additional, Hiremath, Swapnil, additional, Horwitz, Edward J., additional, Hou, Susan, additional, Inker, Lesley A., additional, Irazabal, Maria V., additional, Irish, Ashley Bruce, additional, Jhaveri, Kenar D., additional, Jefferson, Jonathan Ashley, additional, Kalantar-Zadeh, Kamyar, additional, Kamil, Elaine S., additional, Kenny, Jon-Emile S., additional, Khoury, Charbel C., additional, Kohli, Jatinder, additional, Kovalik, Eugene C., additional, Kovesdy, Csaba P., additional, Kupin, Warren, additional, Lehrich, Ruediger W., additional, Lerma, Edgar V., additional, Levi, Moshe, additional, Lockridge, Joseph L., additional, Lopez, Jennifer, additional, Macedo, Etienne, additional, Mehrotra, Rajnish, additional, Mehta, Ravindra L., additional, Nachman, Patrick H., additional, Nadai, Carol, additional, Negrea, Lavinia Aura, additional, Nicolle, Lindsay E., additional, Norris, Keith C., additional, Novakovic, Alexander, additional, Olyaei, Ali J., additional, Pal, Sumanta Kumar, additional, Palevsky, Paul M., additional, Patel, Ami M., additional, Patney, Vikram, additional, Perazella, Mark A., additional, Pham, Phuong-Chi T., additional, Pham, Phuong-Thu T., additional, Pryor, Joseph B., additional, S. Ram, C. Venkata, additional, Rahman, MD, Mahboob, additional, Reisinger, Nathaniel, additional, Rocco, Michael V., additional, Ronco, Claudio, additional, Rosenberg, Mark E., additional, Rosner, Mitchell H., additional, Rudnick, Michael R., additional, Sabath, Ernesto, additional, Sarnak, Mark J., additional, Schell, Jane O., additional, Seay, N. Winn, additional, Sedor, John R., additional, Sethi, Akash Nair, additional, Shah, Anuja, additional, Shah, Lori, additional, Sherer, Benjamin A., additional, Singh, Harpreet, additional, Sinniah, Rajalingam, additional, Sloand, James A., additional, Sparks, Matthew A., additional, Sprague, Stuart M., additional, Steigerwalt, Susan Patricia, additional, Sternlicht, Hillel, additional, Stoller, Marshall L., additional, Thomas, Beje, additional, Toka, Hakan R., additional, Topf, Joel M., additional, Torres, Vicente E., additional, Trachtman, Howard, additional, Traynor, Carol, additional, Tucker, Bryan M., additional, Vogt, Beth A., additional, Wanchoo, Rimda, additional, Weir, Matthew R., additional, Whaley-Connell, Adam, additional, Whittier, William L., additional, Wish, Jay B., additional, Wong, Florence, additional, Wymer, David C., additional, Wymer, David T.G., additional, and Zand, Ladan, additional

Published
2019
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12. The Challenges of Treating Cancer Patients on Hemodialysis, or With Chronic Kidney Disease

Author

Khoury, Charbel C. and Steele, David J.R.

Subjects
Cancer patients -- Care and treatment, Hemodialysis -- Methods -- Patient outcomes, Kidney diseases -- Care and treatment, Mortality, Cardiovascular diseases, Chemotherapy, Cancer treatment, Rasburicase, Antineoplastic agents, Morbidity, Chronic kidney failure, Health
Abstract

It is challenging to diagnose, manage, and treat patients who have kidney disease in addition to cancer. Second to cardiovascular disease, cancer represents a major cause of mortality and morbidity [...]

Published
2017

13. List of Contributors

Author

Afshinnia, Farsad, primary, Agarwal, Anupam, additional, Appel, Gerald B., additional, Bagby, Susan P., additional, Bailey, James L., additional, Bakris, George L., additional, Barrett, Brendan J., additional, Bauer, Carolyn A., additional, Berl, Tomas, additional, Berns, Jeffrey S., additional, Bomback, Andrew, additional, Bose, Anirban, additional, Brosius, Frank C., additional, Brown, Lee K., additional, Bushinsky, David A., additional, Busse, Laurence W., additional, Campbell, Ruth C., additional, Cathro, Helen, additional, Chawla, Lakhmir S., additional, Chen, Sheldon, additional, Chertow, Glenn M., additional, Chew, Emily, additional, Chonchol, Michel, additional, Clive, David M., additional, Cohen, Debbie L., additional, Cohen, Lewis M., additional, Cohen, Scott D., additional, Collins, Ashte’ K., additional, Combs, Sara, additional, Correa-Rotter, Ricardo, additional, Cukor, Daniel, additional, Dalal, Monica, additional, Dancik, Tavis, additional, Davenport, Andrew, additional, Davison, Sara, additional, Zeeuw, Dick de, additional, Delanaye, Pierre, additional, Dharia, Sushma M., additional, Dobre, Mirela A., additional, Drawz, Paul, additional, Dreisbach, Albert W., additional, Emmett, Michael, additional, Fanton, John H., additional, Felsenfeld, Arnold J., additional, Fernandez, Hilda, additional, Flessner, Michael F., additional, Freedman, Barry I., additional, Fruchter, Yvette, additional, Furth, Susan L., additional, García-García, Guillermo, additional, Germain, Michael J., additional, Germino, Gregory G., additional, Goligorsky, Michael S., additional, Greenberg, Arthur, additional, Guay-Woodford, Lisa M., additional, Hawkins, Katrina, additional, Herzog, Charles A., additional, Holley, Jean L., additional, Hostetter, Thomas H., additional, House, Andrew A., additional, Hruska, Keith A., additional, Huan, Yonghong, additional, Ibrahim, Hassan N., additional, Imran, Nashat, additional, Iñiguez, Jonathan Chávez, additional, Isom, Robert T., additional, Jablonski, Kristen L., additional, Jhaveri, Kenar D., additional, Johansen, Kirsten, additional, Johnson, Richard J., additional, Junghare, Milind Y., additional, Kang, Duk-Hee, additional, Karadsheh, Feras F., additional, Kari, Jameela, additional, Kasiske, Bertram L., additional, Khoury, Charbel C., additional, Kimmel, Paul L., additional, Kopp, Jeffrey B., additional, Kummer, Andrew, additional, Heerspink, Hiddo J.Lambers, additional, Lerman, Lilach O., additional, Levin, Adeera, additional, Levine, Barton S., additional, Lew, Susie Q., additional, Mandayam, Sreedhar, additional, Mattoo, Tej K., additional, Maynard, Sharon E., additional, Meyer, Timothy W., additional, Mitch, William E., additional, Moss, Alvin H., additional, Moxey-Mims, Marva, additional, Muntner, Paul, additional, Murray, Anne M., additional, Nath, Karl A., additional, Neugarten, Joel, additional, No, Gloria, additional, Pahl, Madeleine V., additional, Paller, Mark S., additional, Palmer, Biff F., additional, Parfrey, Patrick S., additional, Patel, Samir S., additional, Pecoits-Filho, Roberto, additional, Peitzman, Steven J., additional, Peixoto, Aldo J., additional, Pham, Phuong-Chi T., additional, Pham, Phuong-Thu T., additional, Rabelink, Ton J., additional, Radhakrishnan, Jai, additional, Raed, Anas, additional, Raj, Dominic S., additional, Ramirez-Sandoval, Juan Carlos, additional, Reckelhoff, Jane F., additional, Ronco, Claudio, additional, Rosenberg, Mark E., additional, Rosner, Mitchell H., additional, Rovin, Brad, additional, Roy-Chaudhury, Prabir, additional, Ruebner, Rebecca, additional, Rule, Andrew D., additional, Sands, Jeff M., additional, Scheinman, Steven J., additional, Schlanger, Lynn E., additional, Seifert, Michael E., additional, Seliger, Stephen, additional, Singh, Ajay K., additional, Stendahl, John C., additional, Surendran, Kameswaran, additional, Textor, Stephen C., additional, Thadhani, Ravi I., additional, Townsend, Raymond R., additional, Unruh, Mark L., additional, Vassalotti, Joseph A., additional, Vaziri, Nosratola D., additional, Velasquez, Manuel T., additional, Ver Halen, Nisha, additional, Wang, Connie J., additional, Wanner, Christoph, additional, Weber, Marc, additional, Weir, Matthew R., additional, Wing, Maria R., additional, Winn, Michelle P., additional, Wymer, David C., additional, Yee, Jerry, additional, and Ziyadeh, Fuad N., additional

Published
2015
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15. The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-[beta], increases podocyte motility and albumin permeability

Author

Lee, Eun Young, Chung, Choon Hee, Khoury, Charbel C., Yeo, Tet Kin, Pyagay, Petr E., Wang, Amy, and Chen, Sheldon

Subjects
Albuminuria -- Diagnosis, Diabetes -- Diagnosis, Kidneys -- Properties, Transforming growth factors -- Properties, Biological sciences
Abstract

The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert noninflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-[beta] (TGF-[beta]) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-[beta] type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-[beta]-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-[beta] were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF-[beta] signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria. albuminuria; nephropathy; cytoskeleton; diabetes

Published
2009

18. A retrospective study of adult patients with noncirrhotic hyperammonemia

Author

Stergachis, Andrew B., primary, Mogensen, Kris M., additional, Khoury, Charbel C., additional, Lin, Alexander P., additional, Peake, Roy WA., additional, Baker, Joshua J., additional, Barkoudah, Ebrahim, additional, Sahai, Inderneel, additional, Sweetser, David A., additional, Berry, Gerard T., additional, and Krier, Joel B., additional

Published
2020
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23. Visualizing the podocyte with multiphoton microscopy

Author

Khoury, Charbel C., Khayat, Mark F., Yeo, Tet-Kin, Pyagay, Petr E., Wang, Amy, Asuncion, Allan M., Sharma, Kumar, Yu, Weiming, and Chen, Sheldon

Subjects
Male, Mice, Knockout, urogenital system, Podocytes, Green Fluorescent Proteins, Kidney Glomerulus, Membrane Proteins, urologic and male genital diseases, Article, Mice, Microscopy, Fluorescence, Multiphoton, Animals, Female, Gene Knock-In Techniques
Abstract

The podocyte is a highly specialized kidney glomerular epithelial cell that plays an essential role in glomerular filtration and is believed to be the target of numerous glomerular diseases leading to proteinuria. Despite the leaps in our understanding of podocyte biology, new methodologies are needed to facilitate research into the cell. Multiphoton microscopy (MPM) was used to image the nephrin knockout/green fluorescent protein (GFP) knock-in heterozygote (Nphs1(tm1Rkl)/J) mouse. The nephrin promoter restricts GFP expression to the podocytes that fluoresce green under excitation. From the exterior of an intact kidney, MPM can peer into the renal parenchyma and visualize the podocytes that outline the globular shape of the glomeruli. Details as fine as the podocyte's secondary processes can be resolved. In contrast, podocytes exhibit no fluorescence in the wildtype mouse and are invisible to MPM. Phenotypically, there are no significant differences between wildtype and Nphs1(tm1Rkl)/J mice in body weight, urinary albumin excretion, creatinine clearance, or glomerular depth. Interestingly, the glomeruli are closer to the kidney capsule in female mice, making the gender the preferred choice for MPM. For the first time, green fluorescent podocytes in a mouse model free of confounding phenotypes can be visualized unequivocally and in the "positive" by MPM, facilitating intravital studies of the podocyte.

Published
2012

25. De novo NAD+biosynthetic impairment in acute kidney injury in humans

Author

Poyan Mehr, Ali, Tran, Mei T., Ralto, Kenneth M., Leaf, David E., Washco, Vaughan, Messmer, Joseph, Lerner, Adam, Kher, Ajay, Kim, Steven H., Khoury, Charbel C., Herzig, Shoshana J., Trovato, Mary E., Simon-Tillaux, Noemie, Lynch, Matthew R., Thadhani, Ravi I., Clish, Clary B., Khabbaz, Kamal R., Rhee, Eugene P., Waikar, Sushrut S., Berg, Anders H., and Parikh, Samir M.

Abstract

Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+fell, quinolinate rose, and QPRT declined. QPRT+/−mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD+metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD+biosynthesis may be a feature of high-risk hospitalizations for which NAD+augmentation could be beneficial.

Published
2018
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28. The monocyte chemoattractant protein-1/CCR2 ioop, inducible by TGF-β, increases podocyte motility and albumin permeability.

Author

Eun Young Lee, Choon Hee Chung, Khoury, Charbel C., Tet Kin Yeo, Pyagay, Petr E., Wang, Amy, and Chen, Sheldon

Subjects
PERMEABILITY, CHEMOKINES, CELL receptors, ALBUMINURIA, CELL motility, ALBUMINS, MONOCYTES
Abstract

The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert noninflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-β (TGF-β) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-β type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-β-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-β were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF-β signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria. [ABSTRACT FROM AUTHOR]

Published
2009
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29. Angiogenic factors.

Author

Khoury CC and Ziyadeh FN

Subjects
Animals, Humans, Vascular Endothelial Growth Factor Receptor-1 physiology, Vascular Endothelial Growth Factor Receptor-2 physiology, Angiopoietins physiology, Diabetic Nephropathies etiology, Vascular Endothelial Growth Factor A physiology
Abstract

Diabetic nephropathy (DN) is in essence a microvascular disease that develops as a result of a confluence of hemodynamic and metabolic perturbations. Angiogenic factors are prime candidates to explain the vascular and pathologic findings of DN; however, analysis of their pathophysiology shows that they have a constellation of effects on the glomerulus that go beyond angiogenesis. Vascular endothelial growth factor (VEGF) is an exemplary candidate for fulfilling the criteria for Koch's postulate as an etiologic agent of the glomerulopathy in diabetes. Its expression and signaling in the kidney are amplified early on in the diabetic state. Moreover, counteracting its effects reverses the albuminuria and other hemodynamic and structural features of experimental DN. Finally, experimental overexpression of VEGF in adult mice replicates several aspects of diabetic kidney disease. Under the influence of a variety of diabetic mediators, the podocyte becomes the main source of increased expression of VEGF in the kidney. The cytokine then exerts its multitude of effects in an autocrine fashion on the podocyte itself, on the endothelial cell in a paracrine manner, and finally contributes to macrophage recruitment acting as a chemokine. The angiopoietins consist primarily of two main factors acting in contrast to each other: Ang1--an antiangiogenic ligand, and Ang2--its competitive inhibitor. Both, however, seem to have important roles in the maintenance of glomerular homeostasis. Diabetes disrupts the tight balance that controls angiopoietin expression and functions and decreases theAng1/Ang2 ratio. The end physiologic result seems to be dependent on the concomitant VEGF changes in the kidney. Because of the intricacy of their control, angiogenic factors are difficult to manipulate therapeutically. However, they remain valid target points for the treatment of DN., (Copyright © 2011 S. Karger AG, Basel.)

Published
2011
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