Early Loss of Peritubular Capillaries after Kidney Transplantation

Steegh, Floortje M.E.G.; Gelens, M.; Nieman, Fred; Hooff, J. P. van; Cleutjens, Jack P.M.; Suylen, Robert Jan van; Daemen, Mat J.A.P.; Heurn, Ernst L.W. van; Christiaans, Maarten H. L.; Peutz‐Kootstra, Carine J.

doi:10.1681/asn.2010050531

Cited by 62 publications

(64 citation statements)

References 27 publications

(38 reference statements)

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“…4,5 Decreased peritubular capillary density in obstructed kidneys of NOX4 KO animals may significantly contribute to increased fibrosis through enhanced local hypoxia. This alteration of microvascularization is in line with the role of NOX4 in angiogenesis described in the heart 15 as well as in some tumors.…”

Section: Discussionmentioning

confidence: 99%

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NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

Khodo

Dizin

Sossauer³

et al. 2012

Journal of the American Society of Nephrology

126

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NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1a and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD cl1 ) cell line increased TGF-b1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1a and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.

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Section: Discussionmentioning

confidence: 99%

“…These include tubular atrophy, via necrosis or apoptosis, and local hypoxia, due to the loss of peritubular capillaries, which are early events. [3][4][5] Tubular cells are both targets of tubulointerstitial fibrosis and important players in its progression via secretion of chemotactic factors and cytokines.…”

mentioning

confidence: 99%

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

Khodo

Dizin

Sossauer³

et al. 2012

Journal of the American Society of Nephrology

126

View full text Add to dashboard Cite

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“…Other studies have also found that progression of IF is particularly prominent early after transplantation (365), suggesting that this is a window for therapeutic intervention. Additional analyses might further improve the predictive value of allograft biopsies such as the immunohistochemical detection of CD44 and vimentin (366), activation markers of parietal epithelial cells as markers of FSGS in the renal transplant (367), or immunohistochemistry aided analyses of peritubular capillaries to detect their early and progressive rarefaction in allografts (368). Renal biopsy tissue can also be used for unbiased approaches such as microarray analyses, which may yield diagnostic molecular signatures (213,(369)(370)(371)(372)(373)(374).…”

Section: Diagnosis Of Renal Fibrosismentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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“…[1][2][3] PTC rarefaction is believed to be a central driving force of CKD because capillary rarefaction may result in deficiency of oxygen/nutrient supply to cells and impaired tubular function, which in turn drives kidney injury. Interstitial fibrosis of the kidney exacerbates this problem and progressively replaces damaged parenchymal tissue with nonfunctioning scar tissue.…”

mentioning

confidence: 99%

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

Kida

Ieronimakis

Schrimpf

et al. 2013

Journal of the American Society of Nephrology

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Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 DV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 DV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 DV primary kidney microvascular endothelial cells migrated and proliferated less than wild-type microvascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.

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Early Loss of Peritubular Capillaries after Kidney Transplantation

Cited by 62 publications

References 27 publications

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

Renal Allograft Fibrosis: Biology and Therapeutic Targets

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

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