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Am J Physiol Renal Physiol 285: F1258-F1270, 2003. First published July 22, 2003; doi:10.1152/ajprenal.00145.2003
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Involvement of transforming growth factor-{beta} in regulation of calcium transients in diabetic vascular smooth muscle cells

Kumar Sharma,1 Leo Deelman,2,* Muniswamy Madesh,3,* Bernd Kurz,1 Emilio Ciccone,1 Senthuran Siva,1 Taishan Hu,1 Yanqing Zhu,1 Lewei Wang,1 Robert Henning,2 Xinliang Ma,4 and Gyorgy Hajnoczky3

1Dorrance Hamilton Research Laboratories, Division of Nephrology, Department of Medicine, 3Department of Anatomy, Pathology and Cell Biology, and 4Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and 2Department of Clinical Pharmacology, University of Groningen, 9713 AV Groningen, The Netherlands

Submitted 11 April 2003 ; accepted in final form 16 July 2003

Altered calcium [Ca2+] transients of vascular smooth muscle cells to vasoconstrictors may contribute to altered regulation of blood flow in diabetes. We postulated that diabetes-induced transforming growth factor (TGF)-{beta} production contributes to impaired ANG II response of vascular smooth muscle cells in macrovessels and microvessels. Aortic vascular smooth muscle cells isolated from diabetic rats exhibited markedly impaired ANG II-induced cytosolic calcium [Ca2+] signal that was completely restored by pretreatment with anti-TGF-{beta} antibodies. Similar findings were noted in microvascular smooth muscle cells isolated from preglomerular vessels and cultured in high glucose. The impact of diabetes on [Ca2+] transients was replicated by addition of TGF-{beta}1 and -{beta}2 isoforms to aortic smooth muscle cells in culture and diabetic cells had enhanced production of TGF-{beta}2. In the in vivo condition, TGF-{beta}1 was increased in diabetic glomeruli, whereas TGF-{beta}2 was increased in diabetic aorta. The characteristic increase in glomerular filtration surface area found in diabetic rats was prevented by treatment with anti-TGF-{beta} antibodies, and impaired ANG II-induced aortic ring contraction in diabetic rats was completely restored by anti-TGF-{beta} antibodies. Impaired vascular dysfunction may be partly due to decreased inositol 1,4,5-trisphosphate receptor (IP3R), as reduced type I IP3R expression was found in diabetic aorta and restored by anti-TGF-{beta} antibodies. We conclude that TGF-{beta} plays an important role in the vascular dysfunction of early diabetes by inhibiting calcium transients in vascular smooth muscle cells.

experimental diabetes; microvessels; angiotensin II; intracellular calcium; inositol 1,4,5-trisphosphate receptor; glomerular hypertrophy


Address for reprint requests and other correspondence: K. Sharma, Thomas Jefferson Univ., Suite 353, Jeff Alumni Hall, 1020 Locust St., Philadelphia, PA 19107 (E-mail: kumar.sharma{at}jefferson.edu).




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