title: BMP signaling and podocyte markers are decreased in human diabetic nephropathy in association with CTGF overexpression.
abstract: Diabetic nephropathy is characterized by decreased expression of bone morphogenetic protein-7 (BMP-7) and decreased podocyte number and differentiation. Extracellular antagonists such as connective tissue growth factor (CTGF; CCN-2) and sclerostin domain-containing-1 (SOSTDC1; USAG-1) are important determinants of BMP signaling activity in glomeruli. We studied BMP signaling activity in glomeruli from diabetic patients and non-diabetic individuals and from control and diabetic CTGF(+/+) and CTGF(+/-) mice. BMP signaling activity was visualized by phosphorylated Smad1, -5, and -8 (pSmad1/5/8) immunostaining, and related to expression of CTGF, SOSTDC1, and the podocyte differentiation markers WT1, synaptopodin, and nephrin. In control and diabetic glomeruli, pSmad1/5/8 was mainly localized in podocytes, but both number of positive cells and staining intensity were decreased in diabetes. Nephrin and synaptopodin were decreased in diabetic glomeruli. Decrease of pSmad1/5/8 was only partially explained by decrease in podocyte number. SOSTDC1 and CTGF were expressed exclusively in podocytes. In diabetic glomeruli, SOSTDC1 decreased in parallel with podocyte number, whereas CTGF was strongly increased. In diabetic CTGF(+/-) mice, pSmad1/5/8 was preserved, compared with diabetic CTGF(+/+) mice. In conclusion, in human diabetic nephropathy, BMP signaling activity is diminished, together with reduction of podocyte markers. This might relate to concomitant overexpression of CTGF but not SOSTDC1.
authors.affiliation: Department of Pathology, H04.312, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Tamara
authors.initials: T
authors.lastname: Turk
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Leeuwis
authors.forename: Julia
authors.initials: J
authors.lastname: Gray
authors.forename: Suzy V
authors.initials: SV
authors.lastname: Torti
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lyons
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002452:Cell Count; D002454:Cell Differentiation; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000096:biosynthesis; D008875:Middle Aged; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D019485:Bone Morphogenetic Proteins; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011506:Proteins; C480733:SOSTDC1 protein, human; C503967:SYNPO protein, human; C113267:nephrin; D055513:Connective Tissue Growth Factor