Erwin P Böttinger

Mount Sinai School of Medicine, Manhattan, NY, United States

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Publications (66)440.47 Total impact

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    Erwin P Böttinger
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    ABSTRACT: While erudite cell biologists have for many decades described singular immotile appendages known as primary cilia to be present on most cells in our bodies, cilial function(s) long remained an enigma. Driven largely by an ever increasing number of discoveries of genetic defects in primary cilia during the past decade, cilia were catapulted from a long lasting existence in obscurity into the bright spotlight in cell biology and medicine. The study by O'Toole et al. in this issue of the JCI adds a novel "enzymatic" facet to the rapidly growing information about these little cellular tails, by demonstrating that defects in the XPNPEP3 gene, which encodes mitochondrial and cytosolic splice variants of X-prolyl aminopeptidase 3, can cause nephronophthisis-like ciliopathy. Future studies are in order now to elucidate the cystogenic pathways affected by disrupted enzymatic function of XPNPEP3 in cilia-related cystogenic diseases.
    The Journal of clinical investigation 02/2010; 120(3):660-3. · 15.39 Impact Factor
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    ABSTRACT: TGF-beta regulates differentiation, growth, and apoptosis of podocytes and mediates podocyte depletion in glomerulosclerosis. TGF-beta promotes proapoptotic signaling mediated by Smad3 but also activates prosurvival pathways such as phosphoinositide-3 kinase (PI3K)/AKT; the latter requires the CD2-associated adaptor protein (CD2AP) in podocytes. Whether the opposing activities mediated by Smad proteins and CD2AP involve molecular cross-talk is unknown. Here, we report that CD2AP-dependent early activation of the antiapoptotic PI3K/AKT pathway does not require TGF-beta receptor-regulated Smad2 and Smad3. We found that the C-terminal region of CD2AP interacts directly with the cytoplasmic tail of the TGF-beta receptor type I (TbetaRI) in a kinase-dependent manner and that the interaction between the TbetaRI and the p85 subunit of PI3K requires CD2AP. Consistent with the proapoptotic function of Smad signaling, Smad2/3-deficient podocytes were hyperproliferative and resistant to TGF-beta-induced growth inhibition and apoptosis. In contrast, CD2AP-deficient cells were hypoproliferative and hypersensitive to TGF-beta-induced apoptosis. In vivo, to determine the effects of reduced Smad3 or CD2AP gene dosage on podocyte apoptosis and proteinuria characteristic of TGF-beta1 transgenic mice, we generated TGF-beta1 transgenic mice deficient for Smad3 or heterozygous for CD2AP. Smad3 deficiency ameliorated podocyte apoptosis, and CD2AP heterozygosity increased both podocyte apoptosis and proteinuria. These data define distinct canonical (Smad) and noncanonical (CD2AP/PI3K/AKT) pathways that arise from direct, independent interactions with the TbetaRI and that mediate opposing signals for podocyte death or survival.
    Journal of the American Society of Nephrology 09/2009; 20(10):2127-37. · 8.99 Impact Factor
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    ABSTRACT: Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-beta1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R(2) = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans.
    American Journal Of Pathology 06/2009; 174(6):2073-85. · 4.60 Impact Factor
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    ABSTRACT: Cellular localization determines whether the serine protease HtrA2 exerts pro- or antiapoptotic functions. In contrast to the well-characterized proapoptotic function of cytosolic HtrA2, mechanisms underlying the mitochondrial protective role are poorly understood. Mpv17l is a transmembrane protein previously implicated in peroxisomal reactive oxygen species metabolism and a close homolog of the inner mitochondrial membrane protein Mpv17. Here we demonstrate a previously undescribed direct interaction between Mpv17l and HtrA2 in mitochondria. The interaction is mediated by a PDZ domain and induces protease activation of HtrA2. HtrA2 inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to extracellular inducers of mitochondrial stress. The physiological role of Mpv17l is underscored by the finding that oxidative stress-induced downregulation of Mpv17l is a consistent feature in renal injury models. Our findings identify Mpv17l as a unique interacting protein and regulator of HtrA2 protease mediating antioxidant and antiapoptotic function in mitochondria.
    Proceedings of the National Academy of Sciences 10/2008; 105(37):14106-11. · 9.81 Impact Factor
  • Erwin P Böttinger
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    ABSTRACT: Chronic progressive kidney diseases typically are characterized by loss of differentiated epithelial cells and activation of mesenchymal cell populations leading to renal fibrosis in response to a broad range of diverse renal injuries. Recent evidence has indicated that epithelial microinjury leads to unbalanced epithelial-mesenchymal communication to initiate the fibrotic response. Transforming growth factors beta constitute a large family of cytokines that control key cellular responses in development and tissue repair. Activation of autocrine and paracrine transforming growth factor-beta signaling cascades in the context of epithelial microinjuries initiate a variety of cell type-dependent signaling and activity profiles, including epithelial apoptosis and epithelial-to-mesenchymal transition, that trigger fibrogenic foci and initiate progressive fibrogenesis in chronic renal injury.
    Seminars in Nephrology 06/2007; 27(3):309-20. · 2.83 Impact Factor
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    ABSTRACT: Transforming growth factors betas (TGF-betas) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-betas modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor. After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.
    Gut 06/2007; 56(5):685-92. · 10.73 Impact Factor
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    ABSTRACT: The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr(db/db) (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr(db/db) mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target.
    Diabetes 12/2006; 55(11):3004-12. · 7.90 Impact Factor
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    ABSTRACT: Smad2 is a member of the intracellular mediators that transduce signals from TGF-beta receptors and activin receptors. Targeted inactivation of Smad2 in mice leads to early lethality before gastrulation. It was shown previously that TGF-betaRII deficiency in vivo leads to defects in B cell homeostasis, Ag responsiveness, and IgA class switch recombination of B cells. To investigate the importance of Smad2-mediated signaling in B lymphocytes, we generated a B cell-specific inactivation of Smad2 in mice (bSmad2(-/-)). bSmad2(-/-) mice had normal B cell numbers in the spleen but showed a reduced population of marginal zone B cells. In contrast, B cells in Peyer's patches and peritoneal B-1a cells of bSmad2(-/-) mice were increased in numbers. bSmad2(-/-) mice showed a reduced number of surface-IgA(+) B cells and of IgA-secreting cells in Peyer's patches, decreased levels of IgA in serum, and, after immunization with a T cell-dependent Ag, a reduced IgA response. Class switch recombination to IgA was impaired in Smad2-deficient B cells, when stimulated in vitro with LPS in the presence of TGF-beta. The growth-inhibitory effects of TGF-beta in LPS-stimulated B cells were not affected in Smad2-deficient B cells. In summary, our data indicate a crucial role of Smad2 in mediating signals for the TGF-beta-directed class switch to IgA and the induction of IgA responses in vivo. Other B cell functions like growth-inhibitory signaling, which are known to be regulated by signals via the TGF-betaR, are not affected in Smad2-deficient B cells.
    The Journal of Immunology 03/2006; 176(4):2389-96. · 5.52 Impact Factor
  • Katalin Susztak, Erwin P Böttinger
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    ABSTRACT: Diabetic nephropathy (DNP) develops after latency periods that may vary by several years in approximately one third of patients with diabetes. This diabetic complication is a complex disorder whereby various genetic and environmental factors determine susceptibility and progression to ESRD. Despite rapid research progress, robust predictors to assess prospectively with high precision the risk for DNP in individuals with diabetes are still lacking. Thus, currently available therapies are usually initiated at more advanced stages of DNP characterized by clinically overt manifestations, including increased urinary albumin excretion and decreased glomerular filtration. In addition, although these interventions have proven efficacy in slowing the progression of DNP, they typically cannot prevent ESRD. New insights into the molecular mechanisms that underlie the origin and progression of DNP are emerging rapidly from advanced large-scale genetic and molecular studies in experimental models and humans. Thus, genetic loci that confer risk for albuminuria and/or progression of kidney disease associated with diabetes are being refined to identify the relevant genetic variants in specific genes. Molecular mRNA profiles that are obtained through microarray screens are being validated to elucidate further their potential as molecular markers and to identify new targets for novel preventive or therapeutic approaches aiming at curing DNP. The challenge before the field is to translate the large amount of new genetic and molecular data to empower clinicians and investigators with reliable predictors of DNP for improved design of preventive clinical trials and for individualized clinical management for millions of individuals affected by diabetes worldwide.
    Journal of the American Society of Nephrology 03/2006; 17(2):361-7. · 8.99 Impact Factor
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    ABSTRACT: Smad family proteins Smad2 and Smad3 are activated by transforming growth factor beta (TGF-beta)/activin/nodal receptors and mediate transcriptional regulation. Although differential functional roles of Smad2 and Smad3 are apparent in mammalian development, the relative functional roles of Smad2 and Smad3 in postnatal systems remain unclear. We used Cre/loxP-mediated gene targeting for hepatocyte-specific deletion of Smad2 (S2HeKO) in adult mice and generated hepatocyte-selective Smad2/Smad3 double knockouts by intercrossing AlbCre/Smad2(f/f) (S2HeKO) and Smad3-deficient Smad3ex8/ex8 (S3KO) mice. All strains were viable and had normal adult liver. However, necrogenic CCL4-induced hepatocyte proliferation was significantly increased in S2HeKO compared to Ctrl and S3KO livers, and transplanted S2HeKO hepatocytes repopulated recipient liver at dramatically increased rates compared to Ctrl hepatocytes in vivo. Using primary hepatocytes, we found that TGF-beta-induced G1 arrest, apoptosis, and epithelial-to-mesenchymal transition in Ctrl and S2HeKO but not in S3KO hepatocytes. Interestingly, S2HeKO cells spontaneously acquired mesenchymal features characteristic of epithelial-to-mesenchymal transition (EMT). Collectively, these results demonstrate that Smad2 suppresses hepatocyte growth and dedifferentiation independent of TGF-beta signaling. Smad2 is not required for TGF-beta-stimulated apoptosis, EMT, and growth inhibition in hepatocytes.
    Molecular and Cellular Biology 02/2006; 26(2):654-67. · 5.04 Impact Factor
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    Kremena V Star, Quingbin Song, Andy Zhu, Erwin P Böttinger
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    ABSTRACT: Identifying genes that underlie quantitative trait loci (QTL) is a challenging task. Here, we present a new QTL software system, named QTL MatchMaker. The system is designed to integrate and mine QTL information across human, mouse and rat genomes and to annotate functional genomic data. It combines and organizes information from relevant public databases and publications and integrates QTL, physical, genetic and cytogenetic maps across human, mouse and rat. To make this application available to the research community we have developed a website for high-throughput mapping of expressed sequences to QTL and for selection of candidate genes in the physiological genomics context of complex traits. QTL MatchMaker is accessible at http://pmrc.med.mssm.edu:9090/QTL/jsp/qtlhome.jsp.
    Nucleic Acids Research 02/2006; 34(Database issue):D586-9. · 8.81 Impact Factor
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    ABSTRACT: Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyperglycemia in Ins2(Akita) (Akita) mice with type 1 diabetes and Lepr(db/db) (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37% reduction) and db/db (27% reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular reactive oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapoptotic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apoptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic nephropathy in murine type 1 and type 2 diabetic models.
    Diabetes 02/2006; 55(1):225-33. · 7.90 Impact Factor
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    ABSTRACT: Podocyte depletion occurs in most progressive glomerular diseases and is thought to result from podocyte loss while the remaining podocytes are unable to proliferate. The underlying mechanisms for podocyte growth arrest/differentiation and depletion remain poorly understood but may involve TGF-beta, which is typically upregulated in injured glomeruli. The TGF-beta are multifunctional cytokines that regulate growth, differentiation, and apoptosis in most cells. Determinants of functional specificity of TGF-beta signaling in cell-cycle control and apoptosis remain poorly understood. Using a unique system of conditionally immortalized podocytes, it is demonstrated that autocrine TGF-beta2 induces G0/G1 arrest and differentiation under nonpermissive culture through Smad3-dependent induction of the cyclin-dependent kinase inhibitor p15(Ink4b) (Cdkn2b). When exposed to recombinant TGF-beta1 (or TGF-beta2), nonpermissive culture podocytes switch to G2/M arrest and apoptosis, selectively at advanced TGF-beta concentrations and specifically in association with suppression of Cdkn2b and activation of proapoptotic p38 mitogen-activated protein kinase. Thus, distinct signaling profiles activated in a concentration-dependent manner by TGF-beta were identified. Autocrine TGF-beta2/Smad3/Cdkn2b signaling in podocytes specifies G0/G1 arrest associated with podocyte differentiation, whereas increasing TGF-beta concentrations beyond a critical threshold induces G2/M block and apoptosis associated with selective p38 mitogen-activated protein kinase activation and with suppression of Cdkn2b. In summary, the results suggest a new functional requirement of TGF-beta2 in growth arrest and differentiation of murine podocytes in vitro and demonstrate that a critical TGF-beta concentration threshold may specify a molecular switch to proapoptotic signaling profiles and apoptosis.
    Journal of the American Society of Nephrology 12/2005; 16(11):3211-21. · 8.99 Impact Factor
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    Jiri Zavadil, Erwin P Böttinger
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    ABSTRACT: Remarkable phenotype plasticity of epithelial cells underlies morphogenesis, epithelial repair and tumor invasiveness. Detailed understanding of the contextual cues and molecular mediators that control epithelial plasticity will be required in order to develop viable therapeutic approaches targeting epithelial-to-mesenchymal transition (EMT), an advanced manifestation of epithelial plasticity. Members of the transforming growth factor (TGF-beta) family of growth factors can initiate and maintain EMT in a variety of biological systems and pathophysiological context by activating major signaling pathways and transcriptional regulators integrated in extensive signaling networks. Here we will review the distinct physiological contexts of EMT and the underlying molecular signaling networks controlled by TGF-beta.
    Oncogene 09/2005; 24(37):5764-74. · 8.56 Impact Factor
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    ABSTRACT: Kidney disease is a major complication of diabetes, and poor glycemic control is associated with the development of diabetic nephropathy. The precise mechanisms that lead to diabetic kidney disease still remain largely unknown and are under current investigation. Because glucose transporters in the kidney play an important role in the local maintenance of intracellular glucose and plasma glucose homeostasis, the tissue distribution and regulation of glucose transporter GLUT8, a new member of the glucose transporter family with important functions in cellular survival, were examined. To understand the normal regulation of GLUT8 expression in response to metabolic signals, fasting and feeding conditions were studied. Additionally, GLUT8 expression was studied using two different models of insulin resistance, GLUT4-/- and db/db mice. GLUT8 was localized to glomerular podocytes and tubular epithelial cells in the distal portion of the nephron. Expression of GLUT8 in the kidney was influenced by plasma glucose levels in vivo. Podocytes in kidneys of diabetic db/db mice express higher levels of GLUT8 compared with nondiabetic db/m mice. Because podocytes play an important role in glomerulosclerosis development and high levels of glucose have been shown to induce apoptotic cell death in various kidney cells, these data may provide further insight into the pathogenesis of glomerulosclerosis and diabetic nephropathy.
    American journal of physiology. Renal physiology 08/2005; 289(1):F186-93. · 3.61 Impact Factor
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    ABSTRACT: Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-beta1, both of which are strongly associated with progression of renal disease. Recently, it was reported that Smad2 but not Smad3 regulates TSP-1 expression in response to TGF-beta1 in rat tubular epithelial cells as well as in mouse fibroblasts. This study investigated the role of ERK1/2 and p38 mitogen-activated protein kinases (MAPK). TGF-beta1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-beta1-induced TSP-1 mRNA and protein expression. Next, the cross-talk between Smad2 and ERK1/2 or p38 was examined. Whereas blocking of ERK1/2 or p38 failed to inhibit TGF-beta1-induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-beta1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-beta1 was able to activate p38 but not ERK1/2 in this cell line. In conclusion, TSP-1 expression is regulated by both ERK1/2 and p38 MAPK in rat proximal tubular cells and mouse fibroblasts in response to TGF-beta1. The ERK1/2 activation is dependent on Smad2 activation, whereas the p38 activation occurs independent of Smad2. Because TSP-1 is a major antiangiogenic molecule and an activator of TGF-beta1, this provides an important insight to the mechanism by which TGF-beta1 may mediate interstitial fibrosis and progressive renal disease.
    Journal of the American Society of Nephrology 05/2005; 16(4):899-904. · 8.99 Impact Factor
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    ABSTRACT: Accumulating evidence supports intrinsic genetic susceptibility as an important variable in the progression of diabetic nephropathy in people. Mice provide an experimental platform of unparalleled power for dissecting the genetics of mammalian diseases; however, phenotypic analysis of diabetic mice lags behind that already established for humans. Standardized benchmarks of hyperglycemia, albuminuria, and measurements of renal failure remain to be developed for different inbred strains of mice. The most glaring deficiency has been the lack of a diabetic mouse model that develops progressively worsening renal insufficiency, the sine qua non of diabetic nephropathy in humans. Differences in susceptibility of these inbred strains to complications of diabetes mellitus provide a possible avenue to dissect the genetic basis of diabetic nephropathy; however, the identification of those strains and/or mutants most susceptible to renal injury from diabetes mellitus is lacking. Identification of a mouse model that faithfully mirrors the pathogenesis of DN in humans will undoubtedly facilitate the development of new diagnostic and therapeutic interventions.
    Advances in Chronic Kidney Disease 05/2005; 12(2):128-45. · 2.03 Impact Factor
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    ABSTRACT: Diabetic nephropathy (DNP) is a common complication of type 1 and type 2 diabetes mellitus and the most common cause of kidney failure. While DNP manifests with albuminuria and diabetic glomerulopathy, its progression correlates best with tubular epithelial degeneration (TED) and interstitial fibrosis. However, mechanisms leading to TED in DNP remain poorly understood. We found that expression of scavenger receptor CD36 coincided with proximal tubular epithelial cell (PTEC) apoptosis and TED specifically in human DNP. High glucose stimulated cell surface expression of CD36 in PTECs. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced by glycated albumins (AGE-BSA and CML-BSA) and free fatty acid palmitate through sequential activation of src kinase, and proapoptotic p38 MAPK and caspase 3. In contrast, paucity of expression of CD36 in PTECs in diabetic mice with diabetic glomerulopathy was associated with normal tubular epithelium and the absence of tubular apoptosis. Mouse PTECs lacked CD36 and were resistant to AGE-BSA-induced apoptosis. Recombinant expression of CD36 in mouse PTECs conferred susceptibility to AGE-BSA-induced apoptosis. Our findings suggest a novel role for CD36 as an essential mediator of proximal tubular apoptosis in human DNP. Because CD36 expression was induced by glucose in PTECs, and because increased CD36 mediated AGE-BSA-, CML-BSA-, and palmitate-induced PTEC apoptosis, we propose a two-step metabolic hit model for TED, a hallmark of progression in DNP.
    PLoS Medicine 03/2005; 2(2):e45. · 15.25 Impact Factor
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    ABSTRACT: Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.
    Journal of the American Society of Nephrology 02/2005; 16(1):27-45. · 8.99 Impact Factor
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    ABSTRACT: We have described previously the use of microarray technology to identify novel target genes of TGF-beta (transforming growth factor-beta) signalling in mouse embryo fibroblasts deficient in Smad2 or Smad3 [Yang, Piek, Zavadil, Liang, Xie, Heyer, Pavlidis, Kucherlapati, Roberts and Böttinger (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 10269-10274]. Among the TGF-beta target genes identified, a novel gene with sequence homology to members of the Ras superfamily was identified, which we have designated as RLP (Ras-like protein). RLP is a Smad3-dependent immediate-early TGF-beta target gene, its expression being induced within 45 min. Bone morphogenetic proteins also induce expression of RLP, whereas epidermal growth factor and phorbol ester PMA suppress TGF-beta-induced expression of RLP. Northern-blot analysis revealed that RLP was strongly expressed in heart, brain and kidney, and below the detection level in spleen and skeletal muscles. At the protein level, RLP is approx. 30% homologous with members of the Ras superfamily, particularly in domains characteristic for small GTPases. However, compared with prototypic Ras, RLP contains a modified P-loop, lacks the consensus G2 loop and the C-terminal prenylation site and harbours amino acid substitutions at positions that render prototypic Ras oncogenic. However, RLP does not have transforming activity, does not affect phosphorylation of mitogen-activated protein kinase and is unable to bind GTP or GDP. RLP was found to associate with certain subtypes of the TGF-beta receptor family, raising the possibility that RLP plays a role in TGF-beta signal transduction. Although RLP did not interact with Smads and did not affect TGF-beta receptor-induced Smad2 phosphorylation, it inhibited TGF-beta-induced transcriptional reporter activation, suggesting that it is a novel negative regulator of TGF-beta signalling.
    Biochemical Journal 11/2004; 383(Pt 1):187-99. · 4.65 Impact Factor

Publication Stats

5k Citations
440.47 Total Impact Points

Institutions

  • 2004–2010
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, NY, United States
  • 2005
    • Vanderbilt University
      Nashville, Michigan, United States
    • Polytechnic Institute of New York University
      Brooklyn, New York, United States
  • 1997–2005
    • Albert Einstein College of Medicine
      • • Department of Medicine
      • • Nephrology
      New York City, New York, United States
  • 2002
    • Yeshiva University
      • Division of Nephrology
      New York City, New York, United States
  • 1997–2001
    • National Cancer Institute (USA)
      Maryland, United States
  • 2000
    • University of Cambridge
      • Department of Medicine
      Cambridge, ENG, United Kingdom
  • 1998
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 1996–1998
    • National Institutes of Health
      • Laboratory of Cancer Prevention
      Bethesda, MD, United States
  • 1994
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1992
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, MA, United States