Herbert Y Lin, MD, Ph.D.

TGF-b Signaling and Diabetic Nephropathy

The overall theme of my laboratory is to understand the role of the TGF-β/BMP signaling pathways in health and disease, specifically, diabetic nephropathy, hemochromatosis and anemia of chronic disease.

Soluble TGF-b Receptors in Treatment of Diabetic Nephropathy: Diabetes mellitus is one of the most common causes of end-stage renal disease, accounting for up to one-half of all patients requiring hemodialysis (USRDS 2006). The mechanisms leading to the development of renal dysfunction and the characteristic structural abnormalities seen in diabetic nephropathy are not well understood. An expanding body of evidence that elevated transforming growth factor b (TGF-b) expression may play an important role in the pathogenesis of diabetic renal disease has accumulated. However, the exact roles and relative contributions to pathology of each isoform (TGF-b1, -b2, or –b3) has not been addressed. Most mammalian cells express three abundant high affinity receptors which can bind and be cross-linked to TGF-b: the type I (~53kDa), type II (~65 kDa), and the type III (~100-280 kDa) receptors. While TGF-b1 binds with high affinity (50-500 pM) to the type I, II and III receptors at the cell surface, TGF-b2 binds with high affinity only to the type III receptor while binding poorly to the majority of the type I and type II receptors. The type II receptor and type I receptors are transmembrane proteins with cytosolic domains containing serine/threonine kinases homologous to that found in the activin and several other receptors. The type III receptor is a membrane bound proteoglycan with a short cytoplasmic tail that has no apparent signaling motif. We have engineered soluble extracellular domain TGF-b type II and type III receptors fused to Fc. We show that the sTbRIII?.Fc (lacking GAG attachment sites) has high affinity for TGF-b2, as well as for TGF-b1 and –b3. For this reason, we chose the sTbRIII?.Fc as our receptor to neutralize TGF-b2 signals. We have also shown that the sTbRII-Fc protein can bind TGF-b1 and TGF-b3 but not TGF-b2. Thus, we will compare the effect of treatment of db/db diabetic mice with either sTbRIII?.Fc or sTbRII-Fc (“sparing” of TGF-b) to assess the specific role of TGF-b2 in the development of diabetic nephropathy.

References.

1. Russo LM, del Re E, Brown D, Lin HY. Evidence for a role of TGF-beta in the induction of post-glomerular albuminuria in diabetic nephropathy - amelioration by soluble TGF-β type II receptor. Diabetes. 2007;56(2):380-8.

2. Chen W, Sun CC, Chen S, Meynard D, Babitt JL, Lin HY. A novel validated enzyme-linked immunosorbent assay to quantify soluble hemojuvelin in mouse serum. Haematologica. 2013 Feb;98(2):296-304. PMCID: PMC3561439

3. Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL, Gorbatov R, Sukhova GK, Gerhardt LM, Smyth D, Zavitz CC, Shikatani EA, Parsons M, van Rooijen N, Lin HY, Husain M, Libby P, Nahrendorf M, Weissleder R, Swirski FK. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013;19(9):1166-72. PMCID: PMC3769444

4. Krause DS1, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP, Lezeau S, Attar E, Wu JY, Lin HY, Divieti-Pajevic P, Hasserjian RP, Schipani E, Van Etten RA, Scadden DT. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med. 2013;19(11):1513-7. PMCID: PMC3827980

 

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