BMP Signaling and Podocyte Markers Are Decreased in Human Diabetic Nephropathy in Association With CTGF Overexpression

Tamara Turk ¹, Jan Willem Leeuwis ¹, Julia Gray ¹, Suzy V. Torti ¹, Karen M. Lyons ¹, Tri Q. Nguyen ¹ and Roel Goldschmeding ^1*

¹ Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands (TT,JWL,TQN,RG); Department of Internal Medicine, Clinical Hospital Center Rijeka, Rijeka, Croatia (TT); FibroGen Inc., South San Francisco, California (JG); Department of Biochemistry and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina (SVT); University of California Los Angeles, Los Angeles, California (KML)

^* To whom correspondence should be addressed. E-mail: r.goldschmeding{at}umcutrecht.nl.

Submitted on December 1, 2008
Accepted on 18 February 2009

	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 signalling activity in glomeruli. We studied BMP signalling activity in glomeruli from diabetic patients and non-diabetic individuals and from control and diabetic CTGF^+/+ and CTGF^+/- mice. BMP signalling activity was visualized by 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 to diabetic CTGF^+/+ mice. In conclusion, in human diabetic nephropathy BMP signalling activity is diminished, together with reduction of podocyte markers. This might relate to concomitant overexpression of CTGF but not SOSTDC1.

Key Words: kidney, bone morphogenetic proteins, Smads, connective tissue growth factor, diabetic nephropathy, glomerulus, podocytes, quantitative histochemistry

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