Epithelial Cells; Kidney; Macrophages; Morphogenesis; Nephrology; Physiology
Stem Cell Center, Yale: Stem Cells and Tissue Repair | Tissue Specific Stem Cells
Our laboratory is interested in defining the cellular pathways that regulate kidney epithelial development and repair and determining the effector proteins that mediate the changes that occur during tubule formation, injury and repair. We have found that macrophages are critical regulators of both initial injury and subsequent repair, and that cross-talk between macrophages and surviving tubular cells determines the macrophage expression profile that induces tubule repair. We have identified activation of the phosphoinositide 3-kinase and MAPK pathways as critical regulators of epithelial cell migration and morphogenesis during both development and repair.
Specialized Terms: Nephrology; Acute Kidney Injury; Physiology and integrative medical biology; Epithelial cell migration and morphogenesis; Epithelial cell adhesion; Migration; Branching tubulogenesis
Extensive Research Description
The primary focus of our laboratory is to determine the mechanisms of renal tubule development and repair. When the kidney is injured following ischemia or toxin exposure, the remaining epithelial cells de-differentiate, spread over the denuded basement membrane, divide, and re-arrange themselves in a specific pattern to regenerate functional tubules. This process requires a complex array of events involving rearrangement of cell shape and regulation of cell-matrix and cell-cell interactions. By examining epithelial cell adhesion, migration, and branching tubulogenesis in response to growth factors such as Hepatocyte Growth Factor and chitin's 3-like 1, we are determining the intracellular signaling events critical for tubule formation during kidney development and following injury. We have focused these efforts on the role of activation of specific MAPK isoforms as well as the PI 3-kinase in the regulation of cell morphogenesis and cell-matrix interactions.
In addition, we are examining the role of the innate immune response to kidney injury and found that macrophages home to the injured kidney and initially promote apoptosis of sublethally injured tubular cells. Subsequent macrophage accumulation includes increasing numbers of alternatively activated macrophages that promote the survival and proliferation of the remaining tubular cells to effect tubule repair.
Kidney injury and repair utilize distinct macrophage phenotypes
Lee S., Huen S., Nishio H., Nishio S., Lee H.K., Choi B-S., Ruhrberg C., and Cantley L.G. Kidney injury and repair utilize distinct macrophage phenotypes. J. Am. Soc. Nephrol., 2011; 22(2): 317-326.
Macrophages promote Cyst Growth in Murine Polycystic Kidney Disease
Karihaloo A., Koraishy F., Huen S., Lee Y., Merrick D., Caplan M., Somlo S., and Cantley L.G. Macrophages promote Cyst Growth in Murine Polycystic Kidney Disease. J. Am. Soc. Nephrol., 2011; 22(10):1809-14.
Increased tubular proliferation as an adaptive response to glomerular albuminuria
Guo J-K., Marlier A., Shi H., Shan A., Ardito T.A., Du Z-P, Kashgarian M., Krause D.S., Biemesderfer D., and Cantley L.G. Increased tubular proliferation as an adaptive response to glomerular albuminuria. J.Am.Soc.Nephrol. 2012; 23(3):429-437.
Chitinase 3-like 1 regulates the renal response to ischemic injury and predicts delayed allograft function
Schmidt I., Hall I.E., Kale S., Lee S., Lin S.R., He C.H., Lee Y., Chupp G., Moeckel G., Lee C.G., Elias J.A., Parikh C.R., and Cantley L.G. Chitinase 3-like 1 regulates the renal response to ischemic injury and predicts delayed allograft function. J.Am.Soc.Nephol. 2013; 24(2): 309-19.
Brg1 regulates urothelial cell fate during ureter development
Weiss R.M., Guo S., Shan A., Shi H., Romano R-A., Sinha S., Cantley L.G., Guo J-K. Brg1 regulates urothelial cell fate during ureter development. J.Am.Soc.Nephrol. 2013 24(4):618-26.
The Terminator mouse: a diphtheria toxin receptor knockin mouse strain for rapid and efficient enrichment of desired cell lineages
Guo J-K., Shi H., Koraishy F., Marlier A., Ding Z., Shan A., and Cantley L.G. The Terminator mouse: a diphtheria toxin receptor knockin mouse strain for rapid and efficient enrichment of desired cell lineages. Kid. Int., 2013; 84(5): 1041-1046.
Chitinase 3-like-1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2
He C, Lee C., Dela Cruz C., Lee C-M., Zhou Y., Ahangari F., Ma B., Herzog E., Rosenberg S.A., Modis Y., Parikh C., Schmidt I., Cantley L., and Elias J.A. Chitinase 3-like-1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2. Cell Reports, 2013; 4(4): 830-841.
Met activation is required for early cytoprotection after ischemic kidney injury
Mason S., Hader C., Marlier A., Moeckel G. and Cantley L.G. Met activation is required for early cytoprotection after ischemic kidney injury. J. Am. Soc. Nephrol., 2014; 25(2): 329-337.
Hepatocyte growth factor (Hgf) stimulates low density lipoprotein receptor-related protein (Lrp) 5/6 phosphorylation and promotes canonical Wnt signaling
Koraishy F., D’Alessandri-Silva C., Marlier A., Wu D. and Cantley L.G. Hepatocyte growth factor (Hgf) stimulates low density lipoprotein receptor-related protein (Lrp) 5/6 phosphorylation and promotes canonical Wnt signaling. J. Biol. Chem., 2014; 289(20): 14341-14350.
Casein Kinase 2 maintains cytoplasmic localization of Foxc2
Golden D., and Cantley L.G. Casein Kinase 2 maintains cytoplasmic localization of Foxc2. Oncogene, 2015; in press.
Granulocyte Macrophage Colony Stimulating Factor Promotes Macrophage Alternative Activation After Renal Ischemia/Reperfusion Injury
Huen S.H., Huynh L., Marlier A., Lee Y., Moeckel G.W., and Cantley, L.G. Granulocyte Macrophage Colony Stimulating Factor Promotes Macrophage Alternative Activation After Renal Ischemia/Reperfusion Injury. J. Am. Soc. Nephrol., 2015; in press.
Development of a Targeted Urine Proteome Assay for Kidney Diseases
Cantley L.G., Colangelo C.M., Stone K.L., Chung L., Belcher J. Abbott T., Cantley J.L., Williams K.R. Parikh C. R. Development of a Targeted Urine Proteome Assay for Kidney Diseases. Proteomics Clin. App., 2015; in press
Full List of PubMed Publications
- Montgomery TA, Xu L, Mason S, Chinnadurai A, Lee CG, Elias JA, Cantley LG: Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts. J Am Soc Nephrol. 2017 Nov; 2017 Jul 5. PMID: 28679671
- Williams KR, Colangelo CM, Hou L, Chung L, Belcher JM, Abbott T, Hall IE, Zhao H, Cantley LG, Parikh CR: Use of a Targeted Urine Proteome Assay (TUPA) to identify protein biomarkers of delayed recovery after kidney transplant. Proteomics Clin Appl. 2017 Jul; 2017 Mar 31. PMID: 28261998
- Huen SC, Cantley LG: Macrophages in Renal Injury and Repair. Annu Rev Physiol. 2017 Feb 10. PMID: 28192060
- Puthumana J, Hall IE, Reese PP, Schröppel B, Weng FL, Thiessen-Philbrook H, Doshi MD, Rao V, Lee CG, Elias JA, Cantley LG, Parikh CR: YKL-40 Associates with Renal Recovery in Deceased Donor Kidney Transplantation. J Am Soc Nephrol. 2017 Feb; 2016 Jul 22. PMID: 27451287
- Cantley LG, Colangelo CM, Stone KL, Chung L, Belcher J, Abbott T, Cantley JL, Williams KR, Parikh CR: Development of a Targeted Urine Proteome Assay for kidney diseases. Proteomics Clin Appl. 2016 Jan; 2015 Oct 6. PMID: 26220717
- Huen SC, Huynh L, Marlier A, Lee Y, Moeckel GW, Cantley LG: GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury. J Am Soc Nephrol. 2015 Jun; 2014 Nov 11. PMID: 25388222
- Huen SC, Cantley LG: Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol. 2015 Feb; 2014 Jan 19. PMID: 24442822
- Palmer MB, Vichot AA, Cantley LG, Moeckel GW: Quantification and localization of M2 macrophages in human kidneys with acute tubular injury. Int J Nephrol Renovasc Dis. 2014; 2014 Nov 7. PMID: 25404860
- Hall IE, Stern EP, Cantley LG, Elias JA, Parikh CR: Urine YKL-40 is associated with progressive acute kidney injury or death in hospitalized patients. BMC Nephrol. 2014 Aug 15; 2014 Aug 15. PMID: 25128003
- Koyner JL, Garg AX, Thiessen-Philbrook H, Coca SG, Cantley LG, Peixoto A, Passik CS, Hong K, Parikh CR, TRIBE-AKI Consortium.: Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center study. BMC Nephrol. 2014 Jul 4; 2014 Jul 4. PMID: 24996668
- Koraishy FM, Silva C, Mason S, Wu D, Cantley LG: Hepatocyte growth factor (Hgf) stimulates low density lipoprotein receptor-related protein (Lrp) 5/6 phosphorylation and promotes canonical Wnt signaling. J Biol Chem. 2014 May 16; 2014 Apr 1. PMID: 24692544
- Esquibies AE, Karihaloo A, Quaggin SE, Bazzy-Asaad A, Cantley LG: Heparin binding VEGF isoforms attenuate hyperoxic embryonic lung growth retardation via a FLK1-neuropilin-1-PKC dependent pathway. Respir Res. 2014 Mar 19; 2014 Mar 19. PMID: 24641672
- Guo JK, Shi H, Koraishy F, Marlier A, Ding Z, Shan A, Cantley LG: The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages. Kidney Int. 2013 Nov; 2013 Jun 5. PMID: 23739236
- Huen SC, Moeckel GW, Cantley LG: Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury. Am J Physiol Renal Physiol. 2013 Aug 15; 2013 Jun 12. PMID: 23761668
- Wells EK, Yarborough O 3rd, Lifton RP, Cantley LG, Caplan MJ: Epithelial morphogenesis of MDCK cells in three-dimensional collagen culture is modulated by interleukin-8. Am J Physiol Cell Physiol. 2013 May 15; 2013 Mar 13. PMID: 23485708
- Weiss RM, Guo S, Shan A, Shi H, Romano RA, Sinha S, Cantley LG, Guo JK: Brg1 determines urothelial cell fate during ureter development. J Am Soc Nephrol. 2013 Mar; 2013 Feb 28. PMID: 23449535
- Schmidt IM, Hall IE, Kale S, Lee S, He CH, Lee Y, Chupp GL, Moeckel GW, Lee CG, Elias JA, Parikh CR, Cantley LG: Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function. J Am Soc Nephrol. 2013 Feb; 2013 Jan 4. PMID: 23291472
- Guo JK, Marlier A, Shi H, Shan A, Ardito TA, Du ZP, Kashgarian M, Krause DS, Biemesderfer D, Cantley LG: Increased tubular proliferation as an adaptive response to glomerular albuminuria. J Am Soc Nephrol. 2012 Mar; 2011 Dec 22. PMID: 22193389
- Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, Somlo S, Cantley LG: Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2011 Oct; 2011 Sep 15. PMID: 21921140
- Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, Ruhrberg C, Cantley LG: Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol. 2011 Feb. PMID: 21289217
- Togawa A, Sfakianos J, Ishibe S, Suzuki S, Fujigaki Y, Kitagawa M, Mellman I, Cantley LG: Hepatocyte Growth Factor stimulated cell scattering requires ERK and Cdc42-dependent tight junction disassembly. Biochem Biophys Res Commun. 2010 Sep 17; 2010 Aug 20. PMID: 20728428
- Guo JK, Cantley LG: Cellular maintenance and repair of the kidney. Annu Rev Physiol. 2010. PMID: 20148680
- Ma H, Saenko M, Opuko A, Togawa A, Soda K, Marlier A, Moeckel GW, Cantley LG, Ishibe S: Deletion of the Met receptor in the collecting duct decreases renal repair following ureteral obstruction. Kidney Int. 2009 Oct; 2009 Aug 12. PMID: 19675527
- Ishibe S, Karihaloo A, Ma H, Zhang J, Marlier A, Mitobe M, Togawa A, Schmitt R, Czyczk J, Kashgarian M, Geller DS, Thorgeirsson SS, Cantley LG: Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology. Development. 2009 Jan. PMID: 19103805
- Schmitt R, Marlier A, Cantley LG: Zag expression during aging suppresses proliferation after kidney injury. J Am Soc Nephrol. 2008 Dec; 2008 Sep 24. PMID: 18815245
- Wei F, Karihaloo A, Yu Z, Marlier A, Seth P, Shibazaki S, Wang T, Sukhatme VP, Somlo S, Cantley LG: Neutrophil gelatinase-associated lipocalin suppresses cyst growth by Pkd1 null cells in vitro and in vivo. Kidney Int. 2008 Nov; 2008 Aug 13. PMID: 18974761
- Bi B, Guo J, Marlier A, Lin SR, Cantley LG: Erythropoietin expands a stromal cell population that can mediate renoprotection. Am J Physiol Renal Physiol. 2008 Oct; 2008 Jul 23. PMID: 18653480
- Ishibe S, Cantley LG: Epithelial-mesenchymal-epithelial cycling in kidney repair. Curr Opin Nephrol Hypertens. 2008 Jul. PMID: 18660674
- Shibazaki S, Yu Z, Nishio S, Tian X, Thomson RB, Mitobe M, Louvi A, Velazquez H, Ishibe S, Cantley LG, Igarashi P, Somlo S: Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum Mol Genet. 2008 Jun 1; 2008 Feb 7. PMID: 18263604
- Esquibies AE, Bazzy-Asaad A, Ghassemi F, Nishio H, Karihaloo A, Cantley LG: VEGF attenuates hyperoxic injury through decreased apoptosis in explanted rat embryonic lung. Pediatr Res. 2008 Jan. PMID: 18043510
- Guo JK, Cheng EC, Wang L, Swenson ES, Ardito TA, Kashgarian M, Cantley LG, Krause DS: The commonly used beta-actin-GFP transgenic mouse strain develops a distinct type of glomerulosclerosis. Transgenic Res. 2007 Dec; 2007 Jun 27. PMID: 17594530
- Bi B, Schmitt R, Israilova M, Nishio H, Cantley LG: Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol. 2007 Sep; 2007 Jul 26. PMID: 17656474
- Ishibe S, Haydu JE, Togawa A, Marlier A, Cantley LG: Cell confluence regulates hepatocyte growth factor-stimulated cell morphogenesis in a beta-catenin-dependent manner. Mol Cell Biol. 2006 Dec; 2006 Oct 9. PMID: 17030602
- Grimm DH, Karihaloo A, Cai Y, Somlo S, Cantley LG, Caplan MJ: Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells. J Biol Chem. 2006 Jan 6; 2005 Nov 8. PMID: 16278216
- Cantley LG: Adult stem cells in the repair of the injured renal tubule. Nat Clin Pract Nephrol. 2005 Nov. PMID: 16932361
- Karihaloo A, Karumanchi SA, Cantley WL, Venkatesha S, Cantley LG, Kale S: Vascular endothelial growth factor induces branching morphogenesis/tubulogenesis in renal epithelial cells in a neuropilin-dependent fashion. Mol Cell Biol. 2005 Sep. PMID: 16107693
- Krause D, Cantley LG: Bone marrow plasticity revisited: protection or differentiation in the kidney tubule? J Clin Invest. 2005 Jul. PMID: 16007248
- Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG: Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem. 2005 Mar 4; 2005 Jan 6. PMID: 15637066
- Karihaloo A, Nickel C, Cantley LG: Signals which build a tubule. Nephron Exp Nephrol. 2005; 2005 Feb 22. PMID: 15731568
- Ishibe S, Joly D, Liu ZX, Cantley LG: Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Mol Cell. 2004 Oct 22. PMID: 15494312
- Karihaloo A, Kale S, Rosenblum ND, Cantley LG: Hepatocyte growth factor-mediated renal epithelial branching morphogenesis is regulated by glypican-4 expression. Mol Cell Biol. 2004 Oct. PMID: 15367691
- Ueland JM, Gwira J, Liu ZX, Cantley LG: The chemokine KC regulates HGF-stimulated epithelial cell morphogenesis. Am J Physiol Renal Physiol. 2004 Mar; 2003 Nov 4. PMID: 14600031
- Ishibe S, Joly D, Zhu X, Cantley LG: Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis. Mol Cell. 2003 Nov. PMID: 14636584
- Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG: Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest. 2003 Jul; 2003 Jun 16. PMID: 12824456
- Yu CF, Liu ZX, Cantley LG: ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem. 2002 May 31; 2002 Mar 14. PMID: 11896055
- Liu ZX, Yu CF, Nickel C, Thomas S, Cantley LG: Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin-focal adhesion kinase association. J Biol Chem. 2002 Mar 22; 2002 Jan 9. PMID: 11784715
- Nickel C, Benzing T, Sellin L, Gerke P, Karihaloo A, Liu ZX, Cantley LG, Walz G: The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells. J Clin Invest. 2002 Feb. PMID: 11854320