Exploring mechanisms involved in renal tubular sensing of mechanical stretch following ureteric obstruction

Quinlan, Mark; Docherty, Neil G.; Watson, R. William G.; Fitzpatrick, John M.

doi:10.1152/ajprenal.00576.2007

Cited by 47 publications

(48 citation statements)

References 136 publications

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“…Epithelial stretch is responsible for a wide range of physiologic responses in kidney tubules, including the proliferation of cyst-lining epithelia in polycystic kidney disease (52). Epithelial cell stretch can lead to increased local intracellular calcium concentrations, activation of integrins, focal adhesion kinase, and integrin-linked kinase, signaling an adaptive, strengthening reorganization of the actin cytoskeleton along with thickening of tubular basement membranes (53). Intracellular calcium signaling, as well as cAMP signaling, has also been implicated in acute responses regulating cilia beat rate (22,54).…”

Section: Discussionmentioning

confidence: 99%

The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch

Hellman

Liu

Merkel

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cilia are essential for normal organ function and developmental patterning, but their role in injury and regeneration responses is unknown. To probe the role of cilia in injury, we analyzed the function of foxj1, a transcriptional regulator of cilia genes, in response to tissue damage and renal cyst formation. Zebrafish foxj1a , but not foxj1b , was rapidly induced in response to epithelial distension and stretch, kidney cyst formation, acute kidney injury by gentamicin, and crush injury in spinal cord cells. Obstruction-induced up-regulation of foxj1a was not inhibited by cycloheximide, identifying foxj1a as a primary response gene to epithelial injury. Foxj1 was also dramatically up-regulated in murine cystic kidney disease epithelia [ jck/jck (nek8) and Ift88Tg737Rpw −/− ] as well as in response to kidney ischemia-reperfusion injury. Obstruction of the zebrafish pronephric tubule caused a rapid increase in cilia beat rate that correlated tightly with expanded tubule diameter and epithelial stretch. Zebrafish foxj1a was specifically required for cilia motility. Enhanced foxj1a expression in obstructed tubules induced cilia motility target genes efhc1 , tektin-1 , and dnahc9. foxj1a -deficient embryos failed to up-regulate efhc1 , tektin-1 , and dnahc9 and could not maintain enhanced cilia beat rates after obstruction, identifying an essential role for foxj1 in modulating cilia function after injury. These studies reveal that activation of a Foxj1 transcriptional network of ciliogenic genes is an evolutionarily conserved response to multiple forms of tissue damage and highlight enhanced cilia function as a previously uncharacterized component of organ homeostasis.

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Section: Discussionmentioning

confidence: 99%

The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch

Hellman

Liu

Merkel

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…One attractive candidate is mechanical force. After UUO there is a sudden rise in ureteric and intrarenal pressure, which translates into tubular mechanical stretch (50). Although very little is known about the effects of mechanical stretch on collecting duct epithelial cells, mechanical stretch is known to profoundly affect the function in various cell types (51).…”

Section: Figure 11mentioning

confidence: 99%

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Fujiu

Manabe²,

Nagai³

2011

J. Clin. Invest.

226

209

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Renal tubulointerstitial damage is the final common pathway leading from chronic kidney disease to endstage renal disease. Inflammation is clearly involved in tubulointerstitial injury, but it remains unclear how the inflammatory processes are initiated and regulated. Here, we have shown that in the mouse kidney, the transcription factor Krüppel-like factor-5 (KLF5) is mainly expressed in collecting duct epithelial cells and that Klf5 haploinsufficient mice (Klf5 +/-mice) exhibit ameliorated renal injury in the unilateral ureteral obstruction (UUO) model of tubulointerstitial disease. Additionally, Klf5 haploinsufficiency reduced accumulation of CD11b + F4/80 lo cells, which expressed proinflammatory cytokines and induced apoptosis among renal epithelial cells, phenotypes indicative of M1-type macrophages. By contrast, it increased accumulation of CD11b + F4/80 hi macrophages, which expressed CD206 and CD301 and contributed to fibrosis, in part via TGF-β production -phenotypes indicative of M2-type macrophages. Interestingly, KLF5, in concert with C/EBPα, was found to induce expression of the chemotactic proteins S100A8 and S100A9, which recruited inflammatory monocytes to the kidneys and promoted their activation into M1-type macrophages. Finally, assessing the effects of bone marrow-specific Klf5 haploinsufficiency or collecting duct-or myeloid cell-specific Klf5 deletion confirmed that collecting duct expression of Klf5 is essential for inflammatory responses to UUO. Taken together, our results demonstrate that the renal collecting duct plays a pivotal role in the initiation and progression of tubulointerstitial inflammation.

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“…Mechanical stretch, implicated in the oncoming nephropathy, leads to tubular responses via the activation of ion channels, increases in intracellular calcium levels and cellular apoptosis [53]. …”

Section: Causes Underlying a Reduction In Nephron Numbermentioning

confidence: 99%

The Kidney from Prenatal to Adult Life: Perinatal Programming and Reduction of Number of Nephrons during Development

et al. 2009

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Modified embryonic-fetal development resulting in low birth weight may lead to a reduced nephron endowment, hypertension and renal diseases in adulthood. Regarding the involvement of genetic factors, several environmental conditions may also contribute towards reducing the number of nephrons in the fetus and infant, subsequently constituting a health burden in later life. To date no methods of investigation for the early detection of a reduced nephron reserve are available. However, more structured studies should be implemented to investigate the role of angiotensin-converting enzyme inhibitors in managing proteinurias and glomerulosclerosis in children with renal conditions characterized by reduce nephron number and glomerular hypertrophic changes. In view of the current lack of specific methods of investigation and management, close monitoring of children and young adults at risk of reduced renal reserve should be carried out to enhance the early detection of potential changes in renal function.

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Exploring mechanisms involved in renal tubular sensing of mechanical stretch following ureteric obstruction

Cited by 47 publications

References 136 publications

The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch

The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

The Kidney from Prenatal to Adult Life: Perinatal Programming and Reduction of Number of Nephrons during Development

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