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Department of Pharmacology

Houston, Texas

BCM students are involved in research.
Pharmacology
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Farhad R. Danesh, M.D.

Photo Farhad Danesh, M.D.

Professor
Department of Medicine, Division of Nephrology
Department of Pharmacology

danesh@bcm.edu

Education and Awards

  • M.D., 1990, University of Alcala, Spain
  • Bristol-Myers Squibb Research Award, 1998
  • Northwestern Hospital Intramural Award, 2000
  • Merck Medical School Award, 2001
  • Merck Medical School Award, 2002

Research Interests:

Role of the Rho family of small GTPases in mediating microvascular complications of diabetes

At the cellular level, Rho GTPases (Rho, Rac and Cdc42) control a variety of signal transduction pathways linking plasma membrane receptors to the assembly of the actin cytoskeleton. The actin cytoskeleton plays a central role in driving many of the dynamic aspects of cell behavior, including cell migration, morphogenesis, phagocytosis and cell division. Thus, it is no surprise to find that Rho family members play an important part in regulating many biological activities of the cell. Moreover, by cycling between an inactive GDP-bound and an active GTP-bound state, small GTP-binding proteins function as critical relays in the transduction of a variety of signaling pathways. Many of the Rho-mediated signaling pathways are critical in the pathogenesis of microvascular complications of diabetes such as in diabetic nephropathy. For instance, Rho GTPases promote mesangial hypertrophy, amplify reactive oxygen species by activating NADPH oxidases, and modulate ECM protein degradation and synthesis. My lab is exploring the molecular details of the Rho -initiated pathways that promote kidney fibrosis in the diabetic milieu.

Potential beneficial effects of HMG-CoA reductase inhibitors, also known as statins, in diabetes and its micro/macrovascular complications

While lipid lowering is certainly an important beneficial effect of statins in ameliorating micro/ macrovascular complications of diabetes, pleiotropic effects of statins appear to be just as important. The pleiotropic effects of these drugs include direct beneficial effects on endothelial function, stabilizing atherosclerosis plaques, ameliorating progression of nephropathy and bone disease, and improvement in insulin sensitivity and the development of diabetes. These cholesterol-independent effects of statins primarily stem from the inhibitory effect of statins on mevalonate biosynthesis. By inhibiting L-mevalonic acid, statins also prevent the production of isoprenoids which serve as important lipid attachments for the posttranslational modification of a variety of proteins, including small GTP-binding proteins. My lab is also interested in the pleiotropic effects of statins, and the modulatory effects of statins in various pathobiological pathways involved in diabetes and its complications.

Publications:

  1. Danesh FR, Batlle D: Acquired Lipoprotein (a) excess in patients with renal disease: A marker for cardiovascular risk. Int. J. Cardiovas. Risk Fact. 7:67-75,1997
  2. Danesh FR, Batlle D: H+ ATPase in hyperkalemic distal renal tubular acidosis: Am. J. kidney Dis. 32: 1091-1097, 1998
  3. Keilani T, Danesh FR, Schlueter W, Batlle D: A subdepressor dose of the angiotensin converting enzyme inhibitor, Ramipril, can lower urinary protein excretion without increasing plasma potassium. Am. J. kidney Dis. 33:450-457, 1999
  4. Danesh FR, Klinkmann J, Yokoo H, Ivanovich P: Fatal cervical spondyloarthropathy in a patient with systemic deposition of beta-2 microglobulin amyloid. Am. J. Kidney Dis. 32: 563-566, 1999
  5. Danesh FR, Ye M, Salmi S, Lapointe M, Batlle D: Temporal profile of serum induced S-phase entry and pRb phosphorylation in human skin fibroblasts. Kidney Int. 56:1282-85, 1999
  6. Danesh FR, Ho T: Dialysis Related Amyloidosis. Semin. Dial. 4: 23-26, 2001
  7. Wolf AM, Fragen R, Avram M, Fitzgerald P, Fitzgerald, P, Danesh FR: The pharmokinetics of Dexmedetomidine in volunteers with severe renal impairment. Anesth. Anal. 93: 1205-1209, 2001
  8. Danesh FR, Lynch P, Kanwar YS: Lupus membranous glomerulonephritis mimicking hepatitis C-associated nephropathy. Am. J. Kidney Dis. 39: 3 E23-E26, 2002
  9. Sun L, Pan X, Wada J, Wallner EI, Wuthrich RP, Danesh FR, Chugh S, Kanwar YS: Isolation and characterization of mouse UbA52 gene and its modulation by high-glucose ambience. J. Biol. Chem. 277: 29953-62. 2002
  10. Sun L, Sahai A, Chugh S, Pen X, Wallner E, Danesh FR, Lomasney J, Kanwar YS: High glucose stimulates synthesis of fibronectin via a novel protein kinase C, Rap 1b and B-raf signaling pathway. J. Biol. Chem. 277: 41725-35, 2002
  11. Danesh FR, Sadeghi M, Amro N, Philips C, Sahai A, Lin S, Kanwar Y: 3-Hydrxy-3-methylglutaryl CoA Reductase Inhibitors prevent high glucose induced proliferation of mesangial cells via inhibition of geranylgeranylation of Rho GTPase signaling pathway: Proc. Natl. Acad. Sci. USA, 99, 8301-8305, 2002
  12. Zeng L, Kanwar YS, Amro N, Phillips C, Molitch M, Batlle D, Danesh FR: Epigenetic and genetic analysis of p16 in cultured dermal fibroblasts from type 1 diabetic patients with nephropathy. Kidney Int. 63:2094-2102, 2003
  13. Danesh FR, Anel R, Zeng L, Lomasney J, Kanwar Y: Immunomodulatory effects of HMG-CoA Reductase Inhibitors. Arch. Immunol. Ther. Exp. 51:139-148, 2003
  14. Danesh FR, Wada J, Wallner EI, Sahai A, Srivastava SK, Kanwar YS: Gene regulation of aldose-aldehyde and a renal specific oxidoreductase (RSOS) in the pathobiology of diabetes mellitus. Curr. Med. Chem. 10:1399-1406, 2003
  15. Danesh FR, Kanwar YS: Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy. FASEB J. 18:805-815, 2004
  16. Zeng L, Xu H, Chew TL, Chisholm R, Sadeghi MM, Kanwar YS, Danesh FR: Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated up-regulation of p27. J. Am. Soc. Nephrol. 15:1711–1720, 2004
  17. Kanwar YS, Wada J, Lin S, Danesh FR, Yang Q, Banerjee T, Lomasney JW: Update of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis. Am. J. Physiol. Renal Physiol. 286:F202-215, 2004
  18. Chen S, Lee JS, Iglesia-Dela Cruz MC, Kasama Y, Wang A, Izquirdo-Lahuerta A, Danesh FR, Wolf G, Ziyadeh FN: Angiotensin II stimulates α3(IV) collagen production in mouse podocytes via TGF-ß and VEGF signaling: Implications for diabetic glomeulopathy. Nephrol. Dial. Transplant. 20:1320-1328, 2005
  19. Kanwar YS, Akagi S, Sun L, Nayak B, Xie P, Wada J, Chugh SS, Danesh FR: Cell biology of diabetic kidney disease. Nephron Exp. Nephrol. 101:e100-e110, 2005
  20. Kanwar YS, Nayak B, Lin S, Akagi S, Sun L, Xie P, Wada J, Chugh SS, Danesh FR: Hyperglycemia: its imminent effects on mammalian nephrogenesis. Pediatr. Nephrol. 20:858-866, 2005
  21. Kanwar KS, Akagi S, Nayak B, Lin S, Wada J, Chugh S, Danesh FR: Renal specific oxido-reductase biphasic expression under high glucose ambience during fetal versus neonatal development. Kidney Int. 68:1670-1683, 2005
  22. Shah S, Paparello J, Danesh FR: Effects of statin therapy on the progression of chronic kidney disease. Adv. Chronic Kidney Dis. 12:187-195, 2005
  23. Zeng L, Xu H, Chew TL, Eng E, Chisholm R, Sadeghi MM, Kanwar YS, Danesh FR: Mevalonate pathway modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation. FASEB J. 10.1096/fj.05-4240fje, 2005
  24. Nayak B, Xie P, Akagi S, Yang Q, Sun L, Wada J, Thakur A, Danesh FR, Chugh SS, Kanwar SS: Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience. Proc. Natl. Acad. Sci. USA. 102: 17952-17957, 2005
  25. Xu H, Liu P, Liuqin L, Danesh F R, Yang X, Ye Y, Zhan Z, Yang X, Peng H, Sun L: RhoA mediates TNF-α-induced activation of nuclear factor κ-B in rheumatoid synoviocytes: inhibitory effect of simvastatin. Arthritis Rheum. 54: 3441-3451, 2006
  26. Tramonti G, Xie P, Wallner EI, Danesh FR, Kanwar YS: Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes. Am J Physiol Renal Physiol, 291: F972 - F980, 2006
  27. Xu H, Zeng L, Jones J, Chew TL, Pesce L, Chen S, Kanwar YS, Danesh FR: Mevalonate depletion prevents VEGF-induced “Inside-Out” signaling by preventing RhoA and β1 Integrin activation. Am J Physiol. Renal Physiol. 291: 995-1004, 2006
  28. Kanwar YS, Danesh FR, Chugh SS: Chimerism of the Renal Glomerulus Revisited. J. Am. Soc. Nephrol. 18: 2215 – 2217, 2007
  29. Kanwar YS, Danesh FR, Chugh SS: Contribution of Proteoglycans Towards the Integrated Functions of Renal Glomerular Capillaries: A Historical Perspective. Am. J. Pathol. 171: 9 – 13, 2007
  30. Zeng L, Peng H, Kolavennu V, Sadeghi, MM, Danesh FR: RhoA/ROCK pathway is critically involved in the progression of diabetic nephropathy. Submitted
  31. Peng H, Zeng L, Kolavennu V, Sadeghi, MM, Danesh FR: A Rac1-dependent phosphor-occludin pathway contributes to VEGF-induced endothelial cell permeability: Implications for diabetic nephropathy. Submitted.

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