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Yasphal Kanwar, MD PhD
Professor of Pathology and Medicine
Director, Renal Pathology and Clinical Immunology Laboratory
Ward 6-076
303 E. Chicago Avenue
Chicago, IL 60611
y-kanwar@northwestern.edu
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Phone: (312) 503-0004
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Anatomic Pathology Division
Renal Pathology
Clinical Pathology
Immunology
Medical School
Glancy Medical College (India)
Site of Residency
University of Illinois Hospital
Site of Fellowship
Yale University School of Medicine
Research Interests
The overall focus of our laboratory is to study various pathogenetic mechanisms that are relevant to progressive renal injury during embryonic and adult life with special emphasis on diabetic nephropathy. During the past decade, our laboratory identified several genes that are responsive to high glucose challenge in various murine models of diabetic nephropathy. At present, major efforts are directed towards the investigation of two genes, one of which is related to GTP-binding protein, while the other is an extracellular matrix (ECM) protein known as tubulo-interstitial nephritis antigen (TINag).
The low molecular weight GTP-biding proteins (small G proteins) basically modulate various signaling events via their guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), as a result they recycle between an active GTP-bound and inactive GDP-bound states. Currently we are investigating their positive modulators, such as, GEFs, and negative modulators like cbl an oncogene product. Specifically, we are concentrating on Epac1, a GEF which is responsive to cAMP and modulates cell cycle proteins. In view of Epac1 and cbl biology, the pathways that are affected downstream of these modulators are being delineated with the ultimate goal to define mechanisms that influence the biology of renal glomerular and tubular cells that lead to glomerulosclerosis and tubulointerstitial fibrosis the hallmark characteristics of diabetic nephropathy.
The TINag was originally discovered in renal transplant patients that developed auto-antibodies to this protein and rapidly progressed to renal failure. The concept being that anti-TINag antibodies induce tubulo-interstitial disease that adversely influence renal functions, and such may be the case in other renal diseases which progress to renal failure due to fibrosis of the interstitium, for instance, diabetic nephropathy. Thus, we are investigating the role of TINag in the pathogenesis of diabetic nephropathy where tubulo-interstitium is primarily affected. Basically we are attempting to elucidate the mechanisms that lead to up-regulation of ECM genes and down-regulation of MMP genes which would expectedly result in scarring of the interstitium. An offshoot of the work which is being pursued in our laboratory relates to the nephritogenic potential of the anti-TINag antibodies that induce immune-mediated inflammatory response in the interstitium with homing in of the inflammatory cells, liberation of cytokines and thereby fibrosis. Specially, we are addressing the question as to which region or the epitope of the TINag protein is endowed with the most potent nephritogenic potential similar to what has been recently described in Goodpastures syndrome a glomerular disease mediated by anti-GBM antibodies.
The third project relates to the delineation of the mechanisms that lead to defective branching morphogenesis of the kidney under high glucose ambience keeping in perspective the observations made in Caudal Regression Syndrome in offspring of women with type1 diabetes mellitus, where lower part of the human body maldevelops along with abnormalities of the kidney. We are investigating the relevance of both the signaling as well as the ECM molecules as to how they influence the pathobiology of kidney under high glucose ambience or hyperglycemia during murine development, utilizing a metanephric culture system and KO technologies.
Selected Publications
Nayak B, Xie P, Akagi S, Yang Q, Sun L, Wada J, Thakur A, Danesh FR, Chugh SS, Kanwar YS. Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience. Proc Natl Acad Sci USA 102:17952-7, 2005.
Alvares K, Kanwar YS, Veis A. Expression and potential role of dentin phosphophoryn (DPP) in mouse embryonic tissues involved in epithelial-mesenchymal interactions and branching morphogenesis. Dev Dyn. 235:2980-90, 2006.
Liu G, Clement LC, Kanwar YS, Avila-Casado C, Chugh SS. ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. J Biol Chem. 281:39681-92, 2006
Haruna Y, Kashihara N, Satoh M, Tomita N, Namikoshi T, Sasaki T, Fujimori T, Xie P, Kanwar YS. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc. Natl. Acad. Sci. USA 104:2331-2336, 2007.
Soler MJ, Wysocki J, Ye M, Lloveras J, Kanwar YS, Batlle D.. ACE2 inhibition worsens glomerular injury associated with increased ACE expression in STZ-induced diabetic mice. Kidney Int. 72:614-623, 2007.
Kanwar YS, Danesh FR, Chugh SS. Contribution of proteoglycans towards the integrated functions of renal glomerular capillaries: A historical perspective. Am J Path. 171:9-13, 2007.
Sun L, Xie P, Wada J, Kashihara N, Liu FY, Zhao Y, Kumar D, Chugh SS, Danesh FR, Kanwar YS. Rap1b GTPase ameliorates glucose-induced mitochondrial dysfunction. J Am Soc Nephrol 19:2293-2301, 2008.
Xie P, Sun L, Nayak, B, Haruna Y, Liu FY, Kashihara N, Kanwar YS. C/EBP-beta modulates transcription of tubulointerstitial nephritis antigen in obstructive uropathy. J Am Soc Nephrol 20:807-819, 2009.
View more Publications by Yasphal Kanwar, MD PhD
listed in the National Library of Medicine (PubMed)
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