Bmp in Podocytes Is Essential for Normal Glomerular Capillary Formation

Abstract

Bone morphogenetic protein (BMP) 4 exerts multiple biological effects on kidney and ureter development. To examine the role of BMP4 in glomerular morphogenesis, we generated transgenic mice with altered BMP4 function in podocytes by conferring tissue-specificity with the nephrin (Nphs1) promoter. At birth, Tg(Nphs1-Nog) mice, which had loss of BMP4 function in podocytes, were found to have glomerular microaneurysms, collapsed glomerular capillary tufts, enlarged Bowman's capsules, and fewer normal proximal tubules. Conversely, Tg(Nphs1-Bmp4) mice, which had increased BMP4 function in podocytes, demonstrated defects in glomerular capillary formation, but podocytes were not appreciably affected. The Tg(Nphs1-Nog) and Tg(Nphs1-Bmp4) mice shared morphological characteristics with the previously reported podocyte-specific Vegf-A over-expressing and knockout mice, respectively. Consistent with the morphological similarity, in situ hybridization revealed an intense signal for podocyte expression of Vegf in Tg(Nphs1-Nog) mice, whereas the signal was markedly suppressed in Tg(Nphs1-Bmp4) mice. However, in vitro studies with metanephroi failed to demonstrate a direct interaction between BMP4 or Noggin and VEGF in podocytes. Instead, immunostaining showed that phosphorylated Smads, the mediators of BMP signaling, are present in endothelial and/or mesangial cells, but not in podocytes, within the developing glomeruli. Therefore, this study suggests that podocyte-derived BMP plays an important role in glomerular capillary formation, perhaps by acting on non-podocyte glomerular cells in a paracrine fashion. 19: 685-694, 200819: 685-694, . doi: 10.1681 Bone morphogenic protein 4 (BMP4), a member of the TGF-␤ superfamily of secretory signaling molecules, has important regulatory functions during embryonic development that include establishment of the basic embryonic body plan and morphogenesis of individual organs. 1 Bmp4 homozygous null mutant mice are lethal around gastrulation, forming little or no mesoderm. 2,3 Bmp4 heterozygous (Bmp4 ϩ/Ϫ) mice display various kidney and urinary tract anomalies, including hypo/dysplastic kidneys, ectopic ureterovesical junction and double collecting system. 4,5 These phenotypes in Bmp4 ϩ/Ϫ mice, together with findings in studies using metanephric organ culture system, indicate that BMP4 has multiple biologic functions in the early stages of kidney and urinary tract development that include inhibition of ectopic budding of the ureter, 5,6 stimulation of elongation of the branching ureter, and promotion of the growth of metanephric mesenchyme. Because of the multiple abnor- J Am Soc Nephrol

Mammalian Kidney Development: Principles, Progress, and Projections

“…An elegant series of mutants that varied Vegfa protein production in podocytes highlights the critical role of Vegfa signaling in forming the capillary bed (Eremina et al 2003(Eremina et al , 2007. Glomerular formation is also regulated by Bmp4 in podocytes, and PdgfB/Pdgfrb pathway controls mesangial cell recruitment (Lindahl et al 1998;Ueda et al 2008). The intricate specialization and polarization of podocytes, essential to the elaboration of slit diaphragms, is multifactorial and highly complex.…”

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

“…27 Considering that the renal TGF-b production is provoked by Aldo effects, 27 BMPs may have an antagonistic role in Aldo-induced TGF-b actions leading to amelioration of glomerular sclerosis. Recently, Ueda et al 28 reported that BMP-4 dysfunction in developing podocytes leads to abnormal formation of glomerular capillary tuft. In that study, a BMP-binding protein, noggin-overexpressing mice in podocytes developed glomerular microaneurysms and collapse of glomerular capillary tufts.…”

“…These data suggest that podocyte-derived BMPs have an important role in glomerular capillary formation in a paracrine manner. 28 Given that BMPs act to suppress mesangial cell proliferation in vitro, 15 it is possible that the BMP system in the renal cortex has a role in antagonizing renal injury induced by Aldo and high-salt treatment. We previously reported that Aldo stimulated thymidine incorporation of mesangial cells in a concentration-dependent manner in vitro via MR actions.…”

TGF-β–Activated Kinase 1 Is Crucial in Podocyte Differentiation and Glomerular Capillary Formation

“…49 In addition, blockade of BMP4 function in the transgenic Nephrin-Noggin mice with podocyte-selective expression of BMP inhibitor Noggin caused enlargement of glomerular capillaries or microaneurysms and dilated Bowman's capsules with collapsed glomerular capillary tufts, which were similar to those capillaries and capsules observed in Bmp4 +/2 mice. 50 Nephrin-Noggin mice also showed a decrease in the number of mesangial cells in the glomeruli. Similarly, in the Tak1 Δ/Δ kidney, a major morphologic change found was the enlargement of glomerular capillaries and abnormal capillary development.…”