1. Cells: lymphocytes, macrophages, myofibroblasts
2. Peptides: TGFb , CTGF, FGF, endothelin, VEGF, angiotensin II, aldosterone, bradykinin, Wnt-4, HGF, BMP7, plasminogen system
3. Other mediators: eicosanoids, uric acid, glucose, AGE, ROS
4. Microvascular injury – peritubular capillary drop out -- tissue hypoxia

Pathways of injury to the tubular epithelial cell

1. Apoptosis
2. Glomerular proteinuria: growth factors, albumin
3. Epithelial-mesenchymal transdifferentiation: extracellular signals (TGFb , AGE) and molecular pathways (Smad, RhoA)
4. Podocyte loss -- synechia formation – glomerular ultrafiltrate misdirection a) into and through Bowman's capsule, inducing periglomerular fibrosis b) into tubular basement membrane, compromising tubular epithelial cell integrity (Kriz hypothesis)

Diagnosis

1. Renal biopsy: fibrosis, markers of epithelial-mesenchymal transformation
2. Serum and urine markers: cytokines, matrix molecule fragments

Controversy:
which is the more important contributor to progressive renal dysfunction, cellular injury or fibrosis? Should therapy designed to slow progressive renal injury be targeted to protect cells and restore differentiated functions or reduce matrix accumulation?

New therapeutic approaches – current status

1. Gene therapy: proof of principle
2. Peptides: relaxin, BMP7, interferon-(
3. Small molecules: experimental animal studies and clinical trials

Selected references: reviews from the past 12 months

1. Böttinger EP, Bitzer M. TGF-b signaling in renal disease. J Am Soc Nephrol 13:2600-2610, 2002
2. Buemi M, Senatore M, Corica F, Aloisi A et al. Statins and progressive renal disease. Med Res Rev 22:76-84, 2002
3. Eddy AA. Plasminogen activator inhibitor-1 and the kidney. Am J Physiol Renal Physiol 283:F209-F220, 2002
4. Ina K, Kitamura H, Tatskukawa S, Takayama T et al. Transformation of interstitial fibroblasts and tubulointerstitial fibrosis in diabetic nephropathy. Med Electron Microsc 35:87-95, 2002
5. Kang D-H, Johnson RJ. Vascular endothelial growth factor: a new player in the pathogenesis of renal fibrosis. Curr Opin Nephrol Hypertens 12:43-49, 2003
6. Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubular cells. Curr Opin Nephrol Hypertens 12:25-29, 2002
7. Lund RJ, Davies MR, Hruska KA. Bone morphogenetic protein-7: an anti-fibrotic morphogenetic protein with therapeutic importance in renal disease. Curr Opin Nephrol Hypertens 11:31-36, 2002
8. Murphy M, McMahon R, Lappin DW, Brady HR. Gremlins: is this what renal fibrogenesis has come to? Exp Nephrol 10:241-244, 2002
9. Noronha IL, Fujihara CK, Zatz R. The inflammatory component in progressive renal disease – are interventions possible? Nephrol Dial Transplant 17:363-368, 2002
10. Phillips AO, Steadman R. Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. Histol Histopathol 17:247-252, 2002
11. Schnaper HW, Kopp JB. Renal fibrosis. Front Biosci 8:e68-86, 2003
12. Razzaque MS, Taguchi T. Cellular and molecular events leading to renal interstitial fibrosis. Med Electron Microsc 35: 68-80, 2002
13. Yu L, Noble NA, Border WA. Therapeutic strategies to halt renal fibrosis. Curr Opin Nephrol Hypertens 2:177-181, 2002