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Dr Jinhua Li (NHMRC Peter Doherty Fellow)

Department of Anatomy and Developmental Biology

Endothelial Cells and Kidney Regeneration

Patients who progress to end-stage renal disease (ESRD) require intensive medical support by dialysis or kidney transplantation. The past decade has seen a marked increase in the number of patients with newly-diagnosed ESRD, with the majority of new cases being due to diabetic nephropathy and kidney disease related to renovascular disease and hypertension. Diabetic and non-diabetic glomerular diseases remain the major cause of chronic and ESRD. The severity of glomerulosclerosis and tubulointerstitial fibrosis are strong predictors of the progression to ESRD, making this an important target. Mesangial cells and podocytes are thought to be major mediators of glomerulosclerosis. The importance of glomerular endothelial cells (GEnCs) in glomerular injury has been largely ignored. We are interested in understanding how endothelial cells play their critical roles in the pathogenesis of renal injury and fibrosis and how they might initiate kidney regeneration. We use several experimental animal models to understand how GEnCs and peritubular capillary endothelial cells (PEnCs) play their critical roles in the pathogenesis of glomerular and tubulointerstitial injury and fibrosis. We have generated an endothelial-traceble mouse line, Tie2-Cre;loxp-EGFP mice. Tie2 is an endothelial cell marker. In this mouse line, the expression of EGFP (Enhanced green fluorescent protein) persists in cells of endothelial origin, despite any subsequent phenotypic changes. Current experiments utilise streptozotocin-induced diabetic nephropathy and adriamycin-induced nephrosis and unilateral ureteral obstruction models to investigate the roles of endothelial cells in the pathogenesis and regeneration in different disease settings. We also study the contribution of bone marrow-derived endothelial cells to kidney regeneration together with intracellular mechanism(s) implicated in this process. In another project, we are investigating how a novel and potent lipid mediator plays its critical role in kidney repair, particularly in endothelial cell regeneration. Our studies utilize different molecular biology techniques, confocal microscopy and FACS sorting and analysis to explore the roles of renal endothelial cells in kidney injury and repair in depth.

Grants and Awards

1. Li JH. Contribution of bone marrow-derived cells to renal fibrosis and elucidation of cell signalling mechanisms. NHMRC Project Grant (2007-2009) $411,000. 2. NHMRC Peter Doherty Biomedical Postdoctoral Fellowship. $68,500/year x 4 years (2007-2010). 3. Endothelial progenitor cells in kidney development and their potential application in the treatment of renal disease in mouse. Monash University, Faculty of Medicine, Nursing and Health Sciences Strategic grant (2007) $35,000. 4. Finalist, Amgen Best Basic Science Award. Australia and New Zealand Society of Nephrology, 2008.

Recent Publications

1. Li JH, Campanale NV, Deane JA, Bertram JF, Ricardo SD. Blockade of p38 MAPK and TGF-Beta1/Smad Signaling Pathways Rescues Bone Marrow-derived Peritubular Capillary Endothelial Cells in Adriamycin-induced Nephrosis. J Am Soc Nephrol 2006 Oct;17(10):2799-811. Impact factor 7.150
2. Li JH, Campanale NV, Liang RJ, Deane JA, Bertram JF, Ricardo SD. Inhibition of p38 MAPK and TGF-β1/Smad Signalling Pathways Modulates the Development of Fibrosis in Adriamycin-induced Nephropathy. Am J Pathol 2006 Nov;169(5):1527-40. Impact factor 6.243
3. Li JH, Campanale NV, Deane JA, Bertram JF, Ricardo SD. Modulation of the contribution of Bone Marrow-derived Cells to Renal Repair and the Development of Interstitial Fibrosis. Stem Cells 2007 Mar;25(3):697-706. Impact factor 7.775
4. Li H*, Xu D*, Li JH*, Berndt MC, Liu JP. Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem. 2006 Sep 1;281(35):25588-600. *: Equal contribution. Impact factor 5.676
5. Wang W, Huang XR, Li AG, Liu F, Li JH, Truong LD, Wang XJ, Lan HY. Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7. J Am Soc Nephrol. 2005 May;16(5):1371-83 Impact factor
6. 150 6. Li H, Pinto AR, Duan WZ, Li JH, Toh BH and Liu JP. Telomerase down-regulation does not mediate PC12 pheochromocytoma cell differentiation induced by NGF, but requires MAP kinase signalling. J Neurochem. 2005 Nov;95(3):891-901. Impact factor 4.561 7.
7. Li JH, Wang WS, Huang XR, Oldfield M, Schmidt AM, Cooper ME, and Lan HY. Advanced Glycation End Products Induce Tubular Epithelial-Myofibroblast Transition through the RAGE-ERK1/2 MAP Kinase Signaling Pathway. Am J Pathol 2004, 164:1389–139. Impact factor 6.243
8. Li JH, Huang XR, Zhu HJ, Oldfield M, Cooper M, Truong LD, Johnson RJ, Lan HY. Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. FASEB J. 2004 Jan;18(1):176-8. Impact factor 6.963 9.
9. Li JH, Huang XR, Zhu HJ, Johnson R, Lan HY.Role of TGF-beta signaling in extracellular matrix production under high glucose conditions. Kidney Int. 2003 Jun;63(6):2010-9. Impact factor 4.921
10. Li JH, Zhu HJ, Huang XR, Lai KN, Johnson RJ, Lan HY.Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation. J Am Soc Nephrol. 2002 Jun;13(6):1464-72. Impact factor 7.150
11. Lan HY, Mu W, Tomita N, Huang XR, Li JH, Zhu HJ, Morishita R, Johnson RJ. Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol. 2003 Jun;14(6):1535-48. Impact factor 7.150
12. Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ.Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003 Jun;41(6):1287-93. Impact factor 6.961
13. Takahiko Nakagawa, Li JH, Gabriela Garcia, Wei Mu, Ester Piek, Erwin P. Böttinger, Yan Chen, Hong J Zhu, Duk-Hee Kang, George F. Schreiner, Hui Y. Lan, and Richard J. Johnson. TGF- induces proangiogenic and antiangiogenic effects via parallel but distinct Smad pathways. Kidney Int. 2004 Aug;66(2):605-13. Impact factor 4.921