Therapeutic targets in focal and segmental glomerulosclerosis.
OBJECTIVE
Focal and segmental glomerulosclerosis occurs due to a defect in the glomerular filtration barrier. This review highlights contributions from the past year that have enhanced our understanding of the pathophysiology of focal and segmental glomerulosclerosis with emphasis on discoveries which may lead to the identification of therapeutic targets.


RESULTS
Slit diaphragm proteins have become increasingly important in signal transduction and in mediating downstream events. Actin polymerization occurs after the podocin-nephrin-Neph-1 complex is phosphorylated by Src kinase and Fyn. Recent studies of angiotensin receptor antagonists, corticosteroids and erythropoietin unravel new mechanisms that ameliorate proteinuria by targeting the cell cycle within the podocyte. The discovery that an N-acetylmannosamine kinase (MNK) mutant mouse has glomerulopathy is suggestive that human sialylation pathways may represent therapeutic targets. Proteinuria before podocyte effacement demonstrated in laminin-beta2 null mice highlights the importance of the glomerular basement membrane. Interferon-beta reduced proteinuria in three models of kidney injury, showing greatest effect on glomerular endothelial cells in vitro.


CONCLUSIONS
Basic research has illuminated mechanisms by which classic therapies have antiproteinuric effects directly on the podocyte. As knowledge expands with improved molecular techniques, understanding signaling pathways in health and proteinuric states should lead to potential therapeutic targets in focal and segmental glomerulosclerosis.
Lavin
Peter J
PJ
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gbadegesin
Rasheed
R
Damodaran
Tirupapuliyur V
TV
Winn
Michelle P
MP
D000199:Actins / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D003599:Cytoskeleton / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology; D050199:Podocytes / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism
D000199:Actins