NDT Advance Access published online on October 16, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn570
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Rab 23 is expressed in the glomerulus and plays a role in the development of focal segmental glomerulosclerosis
1 Graduate Institute of Medical Sciences 2 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597 4 Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
Correspondence and offprint requests to: Ann Chen, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC. Tel: +886-2-8792-7008; Fax: +886-2-8792-7009; E-mail: doc31717{at}ndmctsgh.edu.tw and Dr. Hao-Ai Shui, Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Min-Chuan East Road, 6th Section, Taipei, Taiwan, ROC. E-mail: haoai{at}ndmctsgh.edu.tw
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Abstract |
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Background. Rab23, a member of the Rab family of small GTPase, has a function in antagonizing sonic hedgehog signal transduction. Both Rab-family and hedgehog-related proteins are involved in sclerosis and fibrosis in certain pathological states, but their roles in focal segmental glomerulosclerosis (FSGS) remain unclear.
Methods. The FSGS model was established in Balb/c mice by a single injection of adriamycin. Serum, urine and mice kidneys were collected on Days 0, 7, 15 and 20. Western blot analysis was performed to detect the levels of Rab23 in the samples. Immunohistochemistry was used to examine the expressional profiles of Rab23 in kidneys. The expressions of transcripts of Rab23, extracellular matrix (ECM) proteins, and various hedgehog signalling pathway genes in kidneys or mesangial cells were evaluated by real-time RT-PCR. The effect of Rab23 on ECM protein expressions was evaluated by the knockdown or overexpression of Rab23 in mesangial cells.
Results. Our results show that elevations of Rab23 were observed in the urine, but not in the serum, of the FSGS mice. Rab23 and hedgehog signalling pathway genes were constitutively expressed in normal kidneys and were significantly up-regulated in the kidneys of FSGS mice. The basal expression of Rab23 was identified in glomeruli, and mesangial cells displayed obvious elevation of Rab23 in the FSGS state. The knockdown or overexpression of Rab23 affected the collagen expression in cultured mesangial cells.
Conclusions. An autocrine loop of hedgehog signalling could be activated in mesangial cells in the FSGS state, and Rab23 may be elevated to suppress hedgehog signalling and/or influence collagen synthesis. Importantly, Rab23 could serve as a biomarker that indicates the severity of FSGS.
Keywords: biomarker; focal segmental glomerulosclerosis; hedgehog signal transduction; mesangial cells; Rab23
Received for publication: 6. 1.08
Accepted in revised form: 18. 9.08