Metanephric kidney glomerular capillary walls develop from tbe formation of microvasculature, close apposition of immature endothelial and visceral epithelial cells (podocytes), and fusion of a dual basement membrane between these two cell layers. With subsequent capillary loop expansion, additional basement membrane, derived mainly from podocytes, is spliced into the fused GBM. Although many of the morphological features of glomerular development have been described, very little is known about the exact origins of the microvasculature and how basement membrane assembly occurs. The three specific aims in this renewal application will begin to define the cellular and molecular mechanisms operative in glomerulogenesis in vivo. (1) The origins of the glomerular endothelium and mesangium will be determined. This will be accomplished by grafting fetal mouse kidneys from normal/transgenic donors into transgenic/normal host mice. In situ hybridization will define the glomerular cell lineages within these grafts. (2) Binding sites within the developing GBM for certain laminin domains are hypothesized to be important for basement membrane fusion and splicing. This idea will be tested by domain-specific mAb affinity isolation of proteolytic laminin fragments, injection of these into newborn rodents, and immunoelectron microscopy. In addition, a laminin cleaving enzyme identified in developing glomeruli will be characterized and its role in GBM assembly determined. (3) Using antibodies against recombinant laminin cloned from a fetal rat kidney expression library, the cellular origin, distribution, and fate of authentic kidney laminin within the developing glomerulus will be defined. These experiments will provide fundamentally new information on mechanisms of glomerular capillary growth and GBM assembly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK034972-10
Application #
2139443
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-01-01
Project End
1998-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Freeburg, Paul B; Robert, Barry; St John, Patricia L et al. (2003) Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development. J Am Soc Nephrol 14:927-38
Abrahamson, Dale R; Robert, Barry (2003) Derivation and differentiation of glomerular endothelial cells. Nephrol Dial Transplant 18 Suppl 6:vi2-7
Abrahamson, Dale R; Prettyman, A Corinne; Robert, Barry et al. (2003) Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int 63:826-34
Bao, Lihua; Spiller, O Brad; St John, Patricia L et al. (2002) Decay-accelerating factor expression in the rat kidney is restricted to the apical surface of podocytes. Kidney Int 62:2010-21
St John, P L; Abrahamson, D R (2001) Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and -11 chains. Kidney Int 60:1037-46
Robert, B; Abrahamson, D R (2001) Control of glomerular capillary development by growth factor/receptor kinases. Pediatr Nephrol 16:294-301
St John, P L; Wang, R; Yin, Y et al. (2001) Glomerular laminin isoform transitions: errors in metanephric culture are corrected by grafting. Am J Physiol Renal Physiol 280:F695-705
Peti-Peterdi, J; Chambrey, R; Bebok, Z et al. (2000) Macula densa Na(+)/H(+) exchange activities mediated by apical NHE2 and basolateral NHE4 isoforms. Am J Physiol Renal Physiol 278:F452-63
Wang, R; St John, P L; Kretzler, M et al. (2000) Molecular cloning, expression, and distribution of glomerular epithelial protein 1 in developing mouse kidney. Kidney Int 57:1847-59
Robert, B; Zhao, X; Abrahamson, D R (2000) Coexpression of neuropilin-1, Flk1, and VEGF(164) in developing and mature mouse kidney glomeruli. Am J Physiol Renal Physiol 279:F275-82

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