Renal Molecular Research Laboratory
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Renal Molecular Research Laboratory Investigator
Feinstein Institute for Medical Research
Professor of Molecular Medicine
Elmezzi Graduate School of Molecular Medicine
Professor of Medicine
Albert Einstein College of Medicine
Chief, Division of Kidney Diseases and Hypertension
North Shore University Hospital and LIJ Medical Center
100 Community Drive, Great Neck, NY11021
Tel: 516-465-3010
Fax: 516-465-3011
MD from Postgraduate Institute for Medical Education and Research, Chandigarh
Research Overview
Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological entity that is characterized by collapsing variant of focal segmental glomerulosclerosis and microcystic dilatation of tubules. It is predominantly a disease of young African American men. Drug abuse has been considered a risk factor for the development of HIVAN. The long-term goal of our research is to understand and develop strategies to modulate the progression of HIVAN. In addition, we found that HIV-1 protein, Nef, stimulated expression of angiotensinogen in podocytes. Based on these results, we propose that HIV-1 infection leads to the activation of RAAS which can be further enhanced by usage of drugs. We are carrying out research to evaluate the effect of RAAS and drugs on HIVAN pathogenesis and to determine the molecular mechanisms involved in disease progression. The outcome of these studies will help in the development of therapeutic strategies to treat this devastating renal disease. In addition, we are evaluating the involved mechanism of HIV-1 entry both in tubular and glomerular cells. We are also evaluating the role of immune mediated strategies to modulate the course of the progression of renal lesions in HIVAN.
Role of Renin-angiotensin-aldosterone in the development of HIVAN
Studies have shown that inhibition of the production and/or action of one of the components of renin-angiotensin-aldosterone system (RAAS) - Ang II, slows the progression of HIVAN. Interestingly, inhibition of action of other components of RAAS-renin and aldosterone, have also been demonstrated to retard the progression of renal lesions in other models of renal diseases. We hypothesize that inhibition of both renin and aldosterone either alone or in combination with Ang II blockade will provide better outcome in terms of providing protection against the progression of HIVAN. Preliminary data in our laboratory this notion. We intend to confirm these findings and carry out clinical trials in patients with HIVAN
Role of drugs in the development of renal lesions
Preliminary studies in our laboratory indicate that drugs such as morphine induce renal cell injury both in vivo and in vitro. These observations are consistent with a recent report indicating mice receiving morphine developed mesangial cell proliferation and glomerulomegaly after a short course therapy. These findings indicate that drugs have potential to contribute to renal lesions in HIV patients. We also noted that both losartan (an Ang II receptor blocker) and captopril (an agent which blocks the production of Ang II) inhibited morphine-induced renal cell injury (tubular cells and glomerular epithelial cells). Moreover, morphine stimulated production of angiotensinogen (a precursor of Ang II) by renal cells. We plan to evaluate the role of Ang II in drug-induced renal lesions in HIV-1 milieu.
Role of oxidative stress in the development of renal lesions in HIV-1 infection
Our recent preliminary studies in Tg26 (a mouse model of HIVAN) animals have shown that both glomerular and tubular cells showed enhanced generation of reactive oxygen species (ROS). In addition, in in vitro studies, podocytes-transduced with HIV-1 not only showed enhanced expression of p66ShcA but also demonstrated increased generation of ROS; whereas, p66ShcA-deficient podocytes showed attenuated generation of ROS. Interestingly, HIV-1 promoted human podocyte apoptosis which could be prevented by treatment with antioxidants as well as by inducing p66ShcA deficiency. Based on these results we hypothesize that HIV-1 infection in conjunction with Ang II induces oxidative stress in glomerular and tubular epithelial cells which promotes the phosphorylation of p66shcA (Ser-36) and Akt; the latter promotes the activation of mTOR and or Foxo3a pathway(s) which contribute to the phenotypic alterations seen in HIVAN. We intend to prove this hypothesis by elucidating the effect of p66ShcA expression and deficient states on HIVAN pathogenesis and to develop therapeutic strategies to prevent the disease progression.
HIV-1 entry in to kidney cells
For a long time it was not clear whether the pathogenesis of HIVAN was due to HIV infection in the renal cell or due to an indirect effect of the systemically dysregulated immune system. Studies designed to address this issue have shown that expression of the HIV-transgene in renal cells was necessary and sufficient for the development of HIVAN. In addition, increasing evidence supports a role for HIV-1 infection of renal epithelium in the pathogenesis of HIVAN. Recently, we demonstrated that HIV-1 enters into tubular cell via DEC-205 receptors. We are now investing the involved HIV-1 entry mechanism in podocytes.
Lab Members:
Name: Anju Yadav, MD
Position: Postdoctoral Research Fellow
Research: Role of Epithelial mesenchymal dedifferentiation in kidney fibrosis.
E-mail: docanjuyadav@yahoo.com
Name: Dileep Kumar, MD
Position: Postdoctoral Research Fellow
Research: Studies Ang II and Kidney.
E-mail: drdileep77@yahoo.com
Name: Joana Mikulak, PhD
Position: Postdoctoral Research Fellow
Research: HIV-1 infection of kidney cells.
E-mail: j.mikulak@libero.it
Name: Shitij Arora, MD
Position: Postdoctoral Research Fellow
Research: Role apoE in HIV-associated kidney injury.
E-mail: shitij_scoops@yahoo.com
Name: Nicholas Franki, MS
Position: Lab Coordinator
E-mail: nfranki@nshs.edu
Publications
Mikulak J, Teichberg S, Faust T, Schmidtmayerova H, Singhal PC. HIV-1 harboring renal tubular epithelial cell interaction with T cells results in T cell trans-infection. Virology. 385:105-114, 2009.
Vashistha H, Husain M, Kumar D, Yadav A, Arora S, Singhal PC. HIV-1 expression induces tubular cell G2/M arrest and apoptosis. Ren Fail. 30:655-64, 2008.
Mathew JT, Patni H, Chaudhary AN, Liang W, Gupta A, Chander PN, Ding G, Singhal PC. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol. 295:F73-81, 2008.
Jia J, Ding G, Zhu J, Chen C, Liang W, Franki N, Singhal PC. Angiotensin II infusion induces nephrin expression changes and podocyte apoptosis. Am J Nephrol. 28:500-7, 2008
Patni H, Mathew JT, Luan L, Franki N, Chander PN, Singhal PC. Aldosterone promotes proximal tubular cell apoptosis: Role of oxidative stress. Am J Physiol Renal Physiol. 293:F1065-71, 2007.
Krishnan SG, Valderrama E, Wagner JD, Mattana J, Shah HH, Appel G, Singhal PC. Monoclonal gammopathy presenting as recurrent nephrotic syndrome: therapeutic implications. Am J Med Sci. 333:313-6, 2007.
Bhaskaran M, Kapasi AA, Reddy K, Singhal PC. Morphine priming rescues high-dose morphine-induced biological perturbationsJ Infect Dis. 195:1860-9, 2007.
Gitman MD, Hirschwerk D, Baskin CH, Singhal PC. Tenofovir-induced kidney injury. Expert Opin Drug Saf. 6:155-64, 2007.
Hatsukari I, Singh P, Hitosugi N, Messmer D, Valderrama E, Teichberg S, Chaung W, Gross E, Schmidtmayerova H, Singhal PC. DEC-205-Mediated Internalization of HIV-1 Results in the establishment of Silent Infection in Renal Tubular cells J Am Soc Nephrol. 18:780-787, 2007.
Messmer D, Hatsukari I, Hitosugi N, Schmidt-Wolf IG, Singhal PC. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol Med. 12:284-90, 2006.
Bhaskaran M, Radhakrishnan N, Patni H, Singh P, Chaudhary AN, Singhal PC. Dialysis membrane-induced oxidative stress: role of heme oxygenase-1Nephron Exp Nephrol. 2007;105:24-32, 2006.
Kapasi AA, Fan S, Singhal PC. Scatter factor mitigates HIV-1 Gp120-induced human mesangial cell injury.Nephron Exp Nephrol 103:103-108, 2006.
Frenklakh L., Bhat R S, Bhaskaran, M, Sharma S, Sharma M, Dinda A and Singhal PC. Morphine-Induced Degradation of the Host Defense Barrier. Role of Intestinal Mucosal Injury. Dig Dis Sci. 51:318-25, 2006.
Hatsukari I, Hitosugi N, Dinda A, Singhal PC. Morphine modulates monocyte-macrophage conversion phase. Cell Immunol 230:41-48, 2006.
Ashfaq A, Gitman M, Singhal PC. Emerging strategies in patients with end-stage renal disease. Expert Opin Pharmaceut. 14: 1897-2005, 2006.
Bhaskaran M, Radhakrishnan N, Patni N, Singh P, Chaudhary AN. Dialysis membrane-induced oxidative stress: Role of HO-1. Nephron Exp Nephrol 105:24-32, 2006.
Kapasi AA, Fan S, Singhal PC. P300 Modulates HIV-1 Gp120-induced apoptosis in human proximal tubular cells: associated with alteration of TGF-beta and smad signaling.Nephron Exp Nephrol 102:30-38, 2006.
Radhakrishanan N, Bhaskaran M, Singhal PC. Hepatocyte growth factor mudulates h202-induced mesangial cell apoptosis through induction of heme oxygenase-1.Nephron Physiol 101:92-98, 2005.
Dinda A, Gitman M, Singhal PC. Immunomodulatory effect of morphine: therapeutic implications. Expert Opin Drug Saf4:669-675, 2005.
Bhat RS, Bhaskaran M, Mongia N, Hitosugi N, Singhal PC. Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation. J Leukocyte Biol 75:1131-1138, 2004.
Gitman M, Singhal PC. Cocaine Induced Renal Disease. Experts Opinion 2004 Expert Opin Drug Saf 5:441-48, 2004.
Mattana J, Adamidis A, Singhal PC: Nitric oxide in tubulointerstitial nephritides. Seminars in Nephrology 24:345-353, 2004.
Patel J, Bhaskaran M, Manjappa N, Reddy K, Franki N, Singhal PC. Morphihne-induced glomerular epithelial cell apoptosis : Role of oxidativc stress. Am J Physiol 285:F861-F869, 2003.
Mongia A, Bhaskaran M, Reddy K, Manjappa N, Baqi N, Singhal PC. Protease inhibitors modulate apoptosis in mesangial cells derived from a mouse model of HIVAN. Kidney Int 65: 860-870, 2004.
Kapasi AA, SA Coscia, Pandya MP, Singhal PC. Morphine modulates HIV-1 gp160-induced murine macrophage and human monocyte apoptosis by disparate ways. J Neuroimmunol 2004 148:86-96, 2004.
Patel K, Bhaskaran M, Dani, D, Reddy K, Singhal PC. Role of Heme Oxygenase (HO)-1 in Morphine-Modulated Apoptosis and Migration of Macrophages. J Infect Dis. 187: 47-54, 2003.
Kapasi AA, Patel G, Goenka A, Nahar N, Modi N, Bhaskaran M, Reddy K, Franki N, Patel J, Singhal PC. Ethanol Promotes T cell Apoptosis through the Mitochondrial Pathway. Immunol 108:313-320, 2003.
Ding G, Kapasi AA, Franki N, Gibbons N, Kasinath BS, and Singhal PC. Angiotensin II induces glomerular epithelial cell apoptosis. Am J Physiol 283:F173-F180, 2002.
Bhaskaran M, Reddy K, Radhakrishanan N, Ding G, Singhal PC. Angiotensin II induces Apoptosis in Renal Proximal Tubular Cells. Am J Physiol 284:F955-65, 2003.
Singhal PC, Bhaskaran M, Patel J, Patel K, Kasinath BS, Duraisamy S, Frank N, Reddy K, Kapasi AA. Role of P38 Mitogen-acivated protein kinase phosphorylation and Fas-FasL interaction in morphine-induced macrophage apoptosis. J Immunol 168:4025-4033, 2002.
Bhaskaran M, Reddy K, Sharma S, Singh J, Radhakrishnan N, Kapasi A, Singhal PC. Morphine-induced degradation of the host defense barrier: Role of macrophage injury. J Inf Dis 184:1524-1531, 2001.
Nwakoby IE, Reddy K, Patel P, Shah N, Sharma S, Bhaskaran M, Gibbons N, Kapasi A, Singhal PC. Fas-mediated apoptosis of neutrophils in sera of patients with infection. Inf Immun 69:3343-3349, 2001.
Ding G, Franki N, Kapasi AA, Reddy K, Gibbons N, Singhal PC. Tubular cell sensecence and expression of TGF-alpha 1 and p21WAF/CIP1 in tubulointerstitial fibrosis of aging rats. Exp Mol Pathol 70:43-45, 2001.
Kapoor R, Reddy K, Liatsikos EN, Smith AD, Singhal PC. Escherichia coli-human uroepthelial cell interaction products enhance fibroblast migration and matrix accumulation. J Endourol 15:155-159, 2001.
Kapasi AA, Fan S, Singhal PC. Role of 14-3-3, c-Myc/Max, and Akt phosphorylation in HIV-1 gp120-induced mesangial cell proliferation. Am J. Physiol 280:F33-F342, 2001.
Chen Guangping, Paka L, Kako Y, Singhal P, Duan W, Pillarisetti S. A protective role for kidney apolipprotein E: regulation of mesangial cell proliferation and matrix expansion. J Biol Chem 276:49142-49147, 2001.
Singhal PC, Kapasi AA, Franki N, Reddy K. Morphine-induced macrophage apoptosis: the role of transforming growth factor-β. Immunol 100:57-62, 2000.
Kapasi AA, Gibbons N, Mattana J, Singhal PC. Morphine stimulates mesangial cell TNF-β and nitrite production. Inflammation 24:463-475, 2000.
Bank N, Kiroycheva M, Singhal PC, Anthony GM, Suthan GJ, Szabo C. Inhibition of nitric oxide synthase ameliorates cellular injury in sickle cell mouse kidneys. Kidney Int 58:82-89, 2000.
Singhal PC, Sankaran RT, Nahar N, Shah N, Patel P. Vasoactive agents modulate migration of monocytes across glomerular endothelial cells. J Invest Med 48:110-117, 2000.
Singhal PC, Kapasi AA, Reddy K, Franki N, Gibbons N and Ding G. Morphine promotes apoptosis in Jurkat cells. J Leukoc Biol 66:650-658, 1999.
Singhal PC, Reddy K, Ding G, Kapasi A, Franki, N, Ranjan R, Nwakoby IE, and Gibbons N. Ethanol-induced macrophage apoptosis: Role of TGF-ß. J Immunol 162:3031-3036, 1999.
Kapasi A and Singhal PC. Aging splenocyte and thymocyte apoptosis is associated with enhanced expression of p53, bax and caspase-3. Mol Cell Biol Res Commun1: 78-81, 1999.
Margiloff L, Chaplia, Chow A, Singhal PC, Mattana J. Metal-catalyzed oxidation of immunoglobulin impairs Fc receptor mediated binding to macrophages. Free Rad Biol Med 25:780-785, 1998.
Singhal PC, Sharma P, Kapasi A, Reddy K, Franki N, Gibbons N. Morphine enhances macrophage apoptosis. J Immunol 160: 1886-1893, 1998.
Singhal PC, Sharma P, Sanwal V, Prasad A, Kapasi A, Franki N, Reddy K, Gibbons N. Morphine modulates proliferation of kidney fibroblasts. Kidney Int 53: 350-357, 1998.
Mattana J, Margiloff L, Sharma P, Singhal PC. Oxidation of the mesangial matrix metalloproteinase-2 impairs gelatinolytic activity. Inflammation 22: 269-275, 1998
Kapasi A, Bhat P, Singhal PC. Tubular cell and HIV-1 gp120 interaction products promote migration of monocytes. Inflammation 22: 137-144, 1998.
Singhal PC, Franki N, Gibbons N, Reddy K. Matrix-mesangial cell interaction modulates migration of macrophages. J Investig Med 46:453-459, 1998.
Singhal PC, Franki N, Sanwal V, Wagner J, Mattana J. Extracellular matrix modulates mesangial cell apoptosis and mRNA expression of cathepsin-B and tissue transglutaminase. J Cell Biochem 68: 22-30, 1998.
Singhal PC, Gibbons N, Franki N, Krishna Reddy, Sharma P, Bansal V, Mattana J, Wagner JD. Simulated glomerular hypertension promotes mesangial cell apoptosis and expression of cathepsin-B and SGP-2. J Inv Med 46: 42-50, 1998.
Singhal PC, Franki N, Reddy K, Gibbons N, Mattana J, Wagner J. Sex and age modulate macrophage, splenocyte, thymocyte and renal cell apoptosis and expression of SGP-2. J Inv Med 45: 567-575, 1997.
Singhal PC, Sanwal V, Reddy K, Franki N, Gibbons N. Morphine-induced apoptosis of splenocytes is associated with enhanced mRNA expression of cathepsin-B. Inflammation 21:609-617, 1997.
Singhal PC, Sharma P, Franki N, Reddy K, Sanwal V, Gibbons N. HIV-1 gp 160 protein modulates mesangial cell proliferation and apoptosis. Nephron 76:284-295, 1997.
Singhal PC, Sharma P, Singhal M, Kapasi A, Gibbons N. HIV-1 gp 160 protein modulates proximal tubular cell proliferation and matrix synthesis. Cell Physio Biochem 7:43-52, 1997.
Mattana J, Magiloff L, Singhal PC. Metal-catalyzed oxidation of extracellular matrix proteins disrupts integrin-mediated adhesion of mesangial cells. Biochem Biophys Res Com 233:50-55, 1997.
Trachtman H, Futterweit S, Singhal PC, Sankaran R, Franki N. Renal tubular epithelial cell- E. coli interaction products stimulate nitric oxide production in cultured rat renal medullary interstitial and mesangial cells. Res Comm Mol Pathol Pharmacol 94:227-238, 1996.
Singhal PC, Sharma P, Gibbons N, Franki N, Kapasi A, Wagner J. Effect of morphine on renomedullary interstitial cell proliferation and matrix accumulation. Nephron 77:225-234, 1997.
Singhal PC, Sagar P, Gupta S, Arya M, Gupta M, Prasad A, Loona R, Sharma P, Mattana J. Pressure modulates monocyte migration. Am J Hypertension 10: 1297-1301, 1997.
Sagar S, Gibbons N, Valderrama E, Singhal PC. Glomerular metalloprotease activity modulates the development of focal segmental glomerulosclerosis. Clin Nephrol 44:356-361, 1995.
Singhal PC, Sagar S, Garg P. Simulated glomerular pressure modulates mesangial cell 72 kDa metalloproteinase activity. Conn Tis Res 33:257- 63, 1996.
Singhal PC, Mattana J, Garg P, Arya M, Shan Z, Gibbons N. Morphine-induced macrophage activity modulates mesangial cell proliferation and matrix synthesis. Kidney Int 49:94-102, 1996.
Trachtman H, Futterweit S, Garg P, Reddy K, Singhal PC. Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. Biochem Boiphys Res Comm 218:704-708, 1996.
Singhal PC, Shan Z, Garg P, Sharma P, Gibbons N. Morphine modulates migration of monocytes. Nephron 73:526-531, 1996.
Sankaran RT, Mattana J, Sharma P, Sharma S, Singhal PC. Escherichia coli-Tubular cell interaction modulates renal medullary interstitial cell proliferation and collagen accumulation. Cell Physiol Biochem 6:223-233, 1996.
Singhal PC, Pan CQ, Sagar S, Valderrama E, Stahal RAK. Morphine modulates mesangial immunoglobulin G uptake in rats with antithymocyte serum-induced mesangial cell injury. Nephron 74:197-203, 1996.
Sharma P, Reddy K, Franki N, Sanwal V, Sankaran R, Ahuja TS, Gibbons N, Mattana J, Singhal PC. Native and oxidized low density ilipoproteins modulate mesangial cell apoptosis. Kidney Int 50:1604-1611, 1996.
Sharma S, Sankararn RT, Shan Z, Gibbons N, Singhal PC. Escherichia coli-Macrophage interactions modulate mesangial cell proliferation and matrix synthesis. Nephron 73:587-596, 1996.
Mattana J, Patel A, Ilunga C, Singhal PC. Furosemide-albumin complexes in refractory nephrotic syndrome and chronic renal failure. Nephron. 73:122-123, 1996.
Mattana J, Sankararn RT, Singhal PC. Increased applied pressure enhances the uptake of IgG complexes by macrophages. Pathobiol 64:40-45, 1996.
Ahuja TS, Mattana J, Valderrama E, Sankaran R, Singhal PC, Waganer JD. Wegener's grnaulomatosis followed by development of sarcoidosis. Am J Kidney Dis 28:893-898, 1996.
Goswami A, Singhal P, Wagner JD, Urivetzky M. Valderrama E, Smith, AD. Matrix modulates uptake of calcium oxalate crystals and cell growth of renal epithelial cells. J Urol. 153:206-211, 1995.
Singhal PC, Sagar S, Garg P. HIV-1 gp160 and 120 proteins modulate mesangial cell gelatinolytic activity. Am J Pathol 147:25-32, 1995.
Mattana J, Sankaran R, Singhal PC. Repetitive mechanical strain suppresses macrophage uptake of immunoglobulin G complexes and enhances cyclic adenosine monophosphate synthesis. Am J Pathol 147: 529-540, 1995.
Singhal PC, Sagar S, Garg P, Bansal V. Vasoactive agents modulate matrix metalloproteinase activity by mesangial cells. Am J Med Sci 310:235-241, 1995.
Trachtman H, Futterweit S, Singhal P. Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. Biochem Biophys Res Comm 207, 120-125, 1995.
Mattana J, Singhal PC. L. Arginine supplementation antagonizes the effects of angiotensin II and endothelin- 1 on mesangial cell proliferation. Cell Physiol Biochem 5:176-192, 1995.
Jaffer S, Mattana J, Singhal PC. Effects of PGE2 on mesangial cell migration. Am J Nephrol 15:300-305, 1995.
Singhal PC, Pan C, Sagar C, E. Valderrama. Effect of morphine on mesangial deposition of ferritin-antiferritin complexes. Nephron 70:229-234, 1995.
Mattana J, Singhal PC. Applied pressure modulates mesangial cell proliferation and matrix synthesis. Am J Hyper 8:1112 1120, 1995.
Li, W., J., Li, M. Ashok, R. Wu, D. Chen, L. Yang, H. Yang, K.J. Tracey, P. Wang, A.E. Sama, and H. Wang. (2007). A cardiovascular drug rescues mice from lethal sepsis by attenuating late-acting proinflammatory mediator, HMGB1. Journal of Immunology 178(6): 3856-3864.
Ivanov, S., A-M, Dragoi, D.V. Essen, J. Louten, G. Yap, Y. Wan, C.A. Biron, M.E. Bianchi, H. Wang, and W-M. Chu. (2007). A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 110(6): 1970-1981.
Li, W., M. Ashok, J., Li, H. Yang, A.E. Sama, and H. Wang. (2007). A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1. PLoS ONE 2(11): e1153.
Tang D., R. Kang, L. Cao, G. Zhang, Y. Yu, W. Xiao, H. Wang, and X. Xiao. (2008). A pilot study to detect HMGB1 and HSP72 in cerebrospinal fluid of pediatric patients with meningitis. Critical Care Medicine 36(1):291-295.
Wang, H., S. Zhu, R. Zhou, W. Li, & A.E. Sama (2008). Therapeutic potential of HMGB1-targeting agents in sepsis. Expert Reviews in Molecular Medicine 10: e32 (1-20).
Wang, H., S. Zhu, M.F. Ward, J. Gong, & A.E. Sama (2008). Hyperglycemia aggravates endotoxin-induced HMGB1 release: yet another reason not to be too sweet. Critical Care Medicine 36(8): 2475-2476.