Number of Glomeruli Is Increased in the Kidney of Transgenic Mice Expressing the Truncated Type II Activin Receptor

Maeshima, Akito; Shiozaki, Shuichi; Tajima, Tomoko; Nakazato, Yoichi; Naruse, Takuji; Kojima, Itaru

doi:10.1006/bbrc.2000.2171

Cited by 28 publications

(20 citation statements)

References 23 publications

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“…Decreased nephron number associated with deletion of one allele has been reported in relation to GDNF (19,20), FGF-7 (29), FGFR1/2 (30), and Pax2 (31) among others. Maeshima et al (10) were the first to report an increase in nephron endowment in relation to decreased signaling, when they found that truncation of the type II Activin receptor (which acts as a dominant negative receptor blocking Activin A signaling) resulted in a dramatic increase in nephron endowment. Activin A is normally an inhibitor of branching morphogenesis (12).…”

Section: Discussionmentioning

confidence: 99%

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Augmented and Accelerated Nephrogenesis in TGF-β2 Heterozygous Mutant Mice

et al. 2008

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Several members of the transforming growth factor-␤ (TGF-␤) superfamily play key roles in kidney development, either directly or indirectly regulating nephron number. Although low nephron number is a risk factor for cardiovascular and renal disease, the implications of increased nephron number has not been examined due to the absence of appropriate animal models. Here, using unbiased stereology we demonstrated that kidneys from TGF-␤2 heterozygous (TGF-␤2 ϩ/Ϫ ) mice have approximately 60% more nephrons than wild-type mice at postnatal day 30. To determine whether augmented nephron number involved accelerated ureteric branching morphogenesis, embryonic day 11.5 metanephroi were analyzed via confocal microscopy. A 40% increase in total ureteric branch length was observed in TGF-␤2 ϩ/Ϫ kidneys, together with an extra generation of branching. In embryonic day 12.5 metanephroi cultured for 48 h the numbers of both ureteric tree tips and glomeruli were significantly greater in TGF-␤2 ϩ/Ϫ kidneys. These findings suggest that augmented nephron number in TGF-␤2 ϩ/Ϫ kidneys results from accelerated ureteric branching morphogenesis and nephron formation. Manipulation of TGF-␤2 signaling in vivo may provide avenues for protection or rescue of nephron endowment in fetuses at risk. T he development of the permanent mammalian kidney (metanephros) is a complex process requiring exquisite temporospatial regulation of multiple cellular events. Much has been learned in the past decade about these molecular regulatory processes (1-4), and the findings from recent microarray studies of gene expression during kidney development, including several studies from our own laboratory, provide much new information about the potential roles of specific genes and gene pathways (5-8).Several members of the transforming growth factor-␤ (TGF-␤) superfamily of signaling molecules have been shown to play key roles in kidney development. These include TGF-␤1 (9), Activin A (10 -12), bone morphogenetic protein 4 (13-15), bone morphogenetic protein 7 (16), and glial cell line-derived neurotrophic factor (GDNF) [reviewed in Shakya et al. (17,18) and 20)]. However, little is known about the role of TGF-␤2 in kidney development. TGF-␤2 protein is expressed earlier in metanephric development than TGF-␤1 and TGF-␤3 (21). TGF-␤2 gene expression has been detected in the kidney at embryonic day (E) 11.5 (22) and the protein localized in and around the ureteric epithelium and nephron structures from E12.5 (21,23). TGF-␤2 homozygous null mutant mice (TGF-␤2 Ϫ/Ϫ ) die within 24 h of birth due to defective lung development (24). The kidneys of these mice display progressive deterioration of the ureteric tubules and an enlarged renal pelvis after E15. No histologic renal phenotype has been reported in TGF-␤2 heterozygous null mutant mice (TGF-␤2 ϩ/Ϫ ). TGF-␤2 has been identified as a candidate molecule that is released from ureteric bud cells aiding in the survival and differentiation of metanephric mesenchyme (MM) (23). In combination with leukemia in...

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Section: Discussionmentioning

confidence: 99%

“…Activin A is normally an inhibitor of branching morphogenesis (12). Maeshima et al (10) hypothesized that alleviating this inhibition would result in increased branching, leading to increased nephron number.…”

Section: Discussionmentioning

confidence: 99%

Augmented and Accelerated Nephrogenesis in TGF-β2 Heterozygous Mutant Mice

et al. 2008

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“…Activin A was shown to inhibit branching morphogenesis of the ureteric bud in an organ culture system (34) as well as in an in vitro tubulogenesis model (35). The number of glomeruli is increased in the kidney of transgenic mice expressing dominantly negative activin type II receptor (36). Collectively, activin A is a negative regulator of tubulogenesis.…”

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confidence: 99%

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Yamashita¹,

Maeshima

Kojima

et al. 2004

Journal of the American Society of Nephrology

130

110

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Abstract. The present study was conducted to examine the involvement of the activin-follistatin system in the fibrotic process of the kidney. Immunoreactive activin A was upregulated in tubular cells in the kidneys with unilateral ureteral obstruction but not in normal and contralateral kidneys. Activin A promoted cell proliferation, enhanced the expression of type I collagen mRNA, and induced the production of ␣-smooth muscle actin in a rat kidney fibroblast cell line (NRK-49F cells) as well as in primary cultured renal interstitial fibroblasts. In contrast, activin A did not affect the expressions of ␣-smooth muscle actin and type I collagen in renal epithelial tubular cell lines LLC-PK1, and MDCK. Follistatin, an antagonist of activin A, significantly inhibited cell proliferation in NRK-49F cells. Blockade of activin signaling by overexpression of truncated type II activin receptor, which lacked the intracellular kinase domain, decreased cell proliferation and reduced the expression level of type I collagen mRNA in NRK-49F cells. The expression of activin A was induced by TGF-␤1 or activin A itself. Induction of type I collagen expression by TGF-␤1 was reduced by follistatin or by overexpression of truncated type II activin receptor. These results suggest that activin A produced by tubular cells acts as a paracrine factor that activates renal interstitial fibroblasts during the fibrotic processes of the kidney.

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“…As an alternative approach to study the physiological role of activins, transgenic mice expressing the truncated type II activin receptor (tActR-II), which acts as a dominant-negative receptor and blocks the action of activins and related ligands, were developed [48]. In these mice, the gross morphological appearance of the kidneys was normal, and the size and wet weight of the kidneys were identical to those of normal mice.…”

Section: Phenotype Of Activins or Activin Receptors Knockout Micementioning

confidence: 99%

“…These data suggest that activin A is a pro-fibrotic cytokine and modulates glomerular matrix expansion during the development of glomerulonephritis. [44,45,46] -Activin A inhibits ureteric bud branching c. Transgenic mice expressing truncated activin mutant receptor [48] -Number of glomeruli was increased in transgenic mice when compared to wild-type mice d. In vitro tubulogenesis model [51] -Blockade of activin action induced branching tubulogenesis 2) Tubular regeneration a. Ischemia-reperfusion injury model [54,62] -Activin A was upregulated in kidney after renal ischemia -Exogenous follistatin enhanced tubular regeneration after renal ischemia and increased the number of Pax-2-positive cells b. Renal tubular epithelial cell line [63] -Activin A inhibited cell proliferation and induced cell differentiation…”

Section: Activin and Renal Fibrosismentioning

confidence: 99%

Activin A: Autocrine Regulator of Kidney Development and Repair

et al. 2008

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Abstract. The research described in this review suggests a novel and important role for activin A in the developmental and repair processes of the kidney ( Table 1). The results obtained in these studies indicate that activin A is a negative regulator of kidney development and plays an essential part in kidney diseases, such as acute renal failure or renal fibrosis. It is also possible that activin A is a key player in the pathophysiological processes of other kidney diseases, such as congenital urogenital abnormalities, renal cystic disease and renal cell carcinoma. Activin A is thus a potential target for therapeutic interventions in kidney diseases. To address this issue, more detailed analysis on the regulation of activin production, modulation of activin activity and activin target genes is required.

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Number of Glomeruli Is Increased in the Kidney of Transgenic Mice Expressing the Truncated Type II Activin Receptor

Cited by 28 publications

References 23 publications

Augmented and Accelerated Nephrogenesis in TGF-β2 Heterozygous Mutant Mice

Augmented and Accelerated Nephrogenesis in TGF-β2 Heterozygous Mutant Mice

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Activin A: Autocrine Regulator of Kidney Development and Repair

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