Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction

Miyajima, Akira; Chen, Jie; Lawrence, C.; Ledbetter, Steve; Soslow, Robert A.; Stern, Joshua M.; Jha, Sharda; Pigato, Joseph; Lemer, Matthew L.; Poppas, Dix P.; Vaughan, E. Darracott; Felsen, Diane

doi:10.1046/j.1523-1755.2000.00414.x

Cited by 311 publications

(302 citation statements)

References 26 publications

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“…Mink lung epithelial cells (MLECs), which were transfected with a PAI-1 promoter driving expression of luciferase in a TGF-␤ 1 responsive manner, were used for analysis of TGF-␤ 1 activity as previously described (Miyajima et al, 2000a). These cells were a generous gift from Dr. Daniel Rifkin.…”

Section: Tgf-␤ Measurementsmentioning

confidence: 99%

Interstitial Fibrosis of Unilateral Ureteral Obstruction is Exacerbated in Kidneys of Mice Lacking the Gene for Inducible Nitric Oxide Synthase

Hochberg

Johnson

Chen

et al. 2000

Laboratory Investigation

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SUMMARY:Unilateral ureteral obstruction (UUO) is characterized by decreases in renal function and increases in interstitial fibrosis. Previous studies have indicated that pharmacologic manipulations that increase nitric oxide (NO) are beneficial to the obstructed kidneys. NO is produced from arginine by nitric oxide synthase (NOS), an enzyme that exists in both constitutive and inducible (iNOS) forms. To determine the role of the inducible form of NOS in UUO, we used mice with a targeted deletion of iNOS (iNOS -/-mice) and compared them with wild-type (WT) mice. Kidneys were obstructed for 2 weeks in both WT and iNOS -/-mice, and were then removed and bisected. Half of the kidney was embedded in paraffin and tissue sections were examined for interstitial volume or the presence of macrophages. The remainder was flash-frozen and samples were used to measure tissue collagen (hydroxyproline) or transforming growth factor-␤ (TGF-␤). This study demonstrates that both cortex and medulla of obstructed kidneys of iNOS -/-mice exhibit significantly increased interstitial volume and interstitial macrophages as compared with their WT counterparts. Furthermore tissue collagen was increased to 9.2 Ϯ 1.3 g/mg tissue in WT obstructed kidneys, whereas in iNOS -/-kidneys, collagen was increased to 13.2 Ϯ 0.8 g/mg tissue. The profibrotic cytokine TGF-␤ was also significantly increased in obstructed kidneys of iNOS -/-mice, as compared with WT mice. No differences were noted between the unobstructed kidneys of iNOS -/-mice compared with WT mice in any of the parameters examined. These results demonstrate that targeted deletion of the iNOS results in exacerbation of fibrotic events in the obstructed kidney. These results confirm previous pharmacologic studies, and suggest that NO produced via the inducible NOS normally serves a protective function in UUO. (Lab Invest 2000, 80:1721-1728.

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Section: Tgf-␤ Measurementsmentioning

confidence: 99%

Interstitial Fibrosis of Unilateral Ureteral Obstruction is Exacerbated in Kidneys of Mice Lacking the Gene for Inducible Nitric Oxide Synthase

Hochberg

Johnson

Chen

et al. 2000

Laboratory Investigation

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“…Overexpression of TGF-␤1 axis is found in virtually every type of chronic renal diseases in experimental animal models and in patients (12)(13)(14). Inhibition of TGF-␤1 signaling by various strategies prevents renal fibrotic lesions and tubular atrophy and attenuates renal dysfunction (15)(16)(17)(18). Conversely, transgenic mice overexpressing TGF-␤1 develop chronic renal disease with increased expression of fibrotic matrix proteins (19,20).…”

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confidence: 99%

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Dai

Yang

Liu

2003

Journal of Biological Chemistry

137

109

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Tubular atrophy resulting from epithelial cell loss is one of the characteristic features in the development of chronic renal interstitial fibrosis. Although the trigger(s) and mechanism for tubular cell loss remain undefined, the hyperactive transforming growth factor (TGF)-␤1 signaling has long been suspected to play an active role. Here we demonstrate that although TGF-␤1 did not induce cell death per se, it dramatically potentiated renal tubular cell apoptosis initiated by other death cues in vitro. Pre-incubation of human kidney epithelial cells (HKC) with TGF-␤1 markedly promoted staurosporine-induced cell death in a time-and dose-dependent manner. TGF-␤1 dramatically accelerated the cleavage and activation of pro-caspase-9, but not procaspase-8, in HKC cells. This event was followed by an accelerated activation of pro-caspase-3. To elucidate the mechanism underlying TGF-␤1 promotion of tubular cell death, we investigated the signaling pathways activated by TGF-␤1. Both Smad-2 and p38 mitogenactivated protein (MAP) kinase were rapidly activated by TGF-␤1, as demonstrated by the early induction of phosphorylated Smad-2 and p38 MAP kinase, respectively. We found that overexpression of inhibitory Smad-7 completely abolished Smad-2 phosphorylation and activation induced by TGF-␤1 but did not inhibit TGF-␤1-induced apoptosis. However, suppression of p38 MAP kinase with chemical inhibitor SC68376 not only abolished p38 MAP kinase phosphorylation but also obliterated apoptosis induced by TGF-␤1. These results suggest that hyperactive TGF-␤1 signaling potentiates renal tubular epithelial cell apoptosis by a Smadindependent, p38 MAP kinase-dependent mechanism.

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“…The deposition and accumulation of collagens I and III are frequently used as markers of fibrosis at later time points following obstruction. [25][26][27][28] Coll IV, on the other hand, is the major component of the basement membrane. Previous studies have demonstrated abnormal expression of Coll IV to be a marker of epithelial injury and tubular remodeling.…”

Section: Interstitial Responsementioning

confidence: 99%

Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

Hiatt

Ivanova

Trnka

et al. 2013

Laboratory Investigation

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Congenital urinary tract obstruction is the single most important cause of childhood chronic kidney disease. We have previously demonstrated that human and primate fetal obstruction impairs the development, differentiation, and maturation of the kidney. Research using postnatal rodent models has primarily focused upon the role of proximal tubular injury, with few reports of collecting duct system pathology or the suitability of the postnatal models for examining injury to the distal nephron. We have employed the mouse unilateral ureteric obstruction (UUO) model and examined time points ranging from 1 to 14 days of obstruction. Many of the key features of fetal collecting duct injury are replicated in the postnatal mouse model of obstruction. Obstruction causes a sixfold increase in myofibroblast accumulation, two-to threefold dilatation of tubules of the distal nephron, 65% reduction of principal cell aquaporin 2 expression, 75% reduction of collecting duct intercalated cell abundance, and disruption of E-cadherin-and bcateninmediated collecting duct epithelial adhesion. Notably, these features are shared by the distal and connecting tubules. This work confirms that distal nephron pathology is a significant component of postnatal mouse UUO. We have highlighted the utility of this model for investigating collecting duct and distal tubule injury and for identifying the underlying mechanisms of the distal nephron's contribution to the repair and fibrosis. Congenital urinary tract obstruction is the single most important cause of chronic kidney disease in children. In the fetus, obstruction of urinary flow during the critical stages of renal nephrogenesis alters branching morphogenesis, decreases nephron endowment, and disrupts normal tubulointerstitial development. [1][2][3][4] We have previously demonstrated that fetal obstruction in the human and primate kidney causes substantial medullary injury, including interstitial expansion, peritubular a smooth muscle actin (aSMA) collar formation, and collecting duct epithelial dysfunction. 1-3 Additional work is required to further identify how medullary and collecting duct injury contributes to and modulates the pathophysiology and progression of injury following obstruction.The rodent unilateral ureteric obstruction (UUO) models are the best-described models of urinary tract obstruction [5][6][7][8][9][10][11][12][13][14][15][16] and are widely used due to their ease of manipulation and the availability of transgenic animals. These models are predominantly postnatal models with much of the work focused on the role of the proximal convoluted tubule and on late time points in which the interstitial and fibrotic responses predominate. [17][18][19][20] Although early changes in tubular hydrodynamics, tubular dilatation, and medullary injury have been briefly described following obstruction, our knowledge of the contributions of these factors and the potential cellular responses they invoke is lacking.We have previously demonstrated that the distal nephron, including the co...

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Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction

Abstract: The present study strongly suggests that an antibody to TGF-beta is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

Cited by 311 publications

References 26 publications

Interstitial Fibrosis of Unilateral Ureteral Obstruction is Exacerbated in Kidneys of Mice Lacking the Gene for Inducible Nitric Oxide Synthase

Interstitial Fibrosis of Unilateral Ureteral Obstruction is Exacerbated in Kidneys of Mice Lacking the Gene for Inducible Nitric Oxide Synthase

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

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