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Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia.

Sanz AB, Sanchez-Niño MD, Izquierdo MC, Jakubowski A, Justo P, Blanco-Colio LM, Ruiz-Ortega M, Egido J, Ortiz A - J. Cell. Mol. Med. (2009)

Bottom Line: In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function.In conclusion, TWEAK actions in tubular cells are context dependent.This may be relevant for compensatory renal hyperplasia following nephrectomy.

View Article: PubMed Central - PubMed

Affiliation: Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.

ABSTRACT
The tumour necrosis factor (TNF) family member TWEAK activates the Fn14 receptor and has pro-apoptotic, proliferative and pro-inflammatory actions that depend on the cell type and the microenvironment. We explored the proliferative actions of TWEAK on cultured tubular cells and in vivo on renal tubules. Additionally, we studied the role of TWEAK in compensatory proliferation following unilateral nephrectomy and in an inflammatory model of acute kidney injury (AKI) induced by a folic acid overdose. TWEAK increased the proliferation, cell number and cyclin D1 expression of cultured tubular cells, in vitro. Exposure to serum increased TWEAK and Fn14 expression and the proliferative response to TWEAK. TWEAK activated the mitogen-activated protein kinases ERK and p38, the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway and NF-kappaB. TWEAK-induced proliferation was prevented by inhibitors of these protein kinases and by the NF-kappaB inhibitor parthenolide. TWEAK-induced tubular cell proliferation as assessed by PCNA and cyclin D1 expression in the kidneys of adult healthy mice in vivo. By contrast, TWEAK knock-out mice displayed lower tubular cell proliferation in the remnant kidney following unilateral nephrectomy, a non-inflammatory model. This is consistent with TWEAK-induced proliferation on cultured tubular cells in the absence of inflammatory cytokines. Consistent with our previously published data, in the presence of inflammatory cytokines TWEAK promoted apoptosis, not proliferation, of cultured tubular cells. In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function. In conclusion, TWEAK actions in tubular cells are context dependent. In a non-inflammatory milieu TWEAK induces proliferation of tubular epithelium. This may be relevant for compensatory renal hyperplasia following nephrectomy.

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TWEAK neutralization decreases apoptosis in tubular epithelium during acute kidney injury (AKI). AKI is characterized by a local inflammatory milieu (15). (A) Time course of apoptosis, assessed by TUNEL and proliferation assessed as PCNA staining. Peak apoptosis precedes peak proliferation. Mean (±S.E.M.) of six animals per group at each time-point. *P < 0.005 versus control. (B) Apoptotic nuclei were stained by TUNEL. TWEAK deficiency decreases TUNEL+ nuclei 24 hrs following induction of AKI. Original magnification ×400. Mean of six animals per group, *P < 0.05 versus TWEAK WT. (C) Active caspase 3 was localized to tubular epithelium 24 hrs following induction of AKI and caspase 3 activation was decreased in TWEAK KO mice. Original magnification ×200. Mean (±S.E.M.) of 4 animals per group. *P < 0.05 versus TWEAK WT. (D) Whole kidney caspase 3 activation 24 hrs following induction of AKI assessed by Western blot of active caspase 3. Representative Western blot and quantification. *P < 0.05 versus TWEAK WT.
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fig10: TWEAK neutralization decreases apoptosis in tubular epithelium during acute kidney injury (AKI). AKI is characterized by a local inflammatory milieu (15). (A) Time course of apoptosis, assessed by TUNEL and proliferation assessed as PCNA staining. Peak apoptosis precedes peak proliferation. Mean (±S.E.M.) of six animals per group at each time-point. *P < 0.005 versus control. (B) Apoptotic nuclei were stained by TUNEL. TWEAK deficiency decreases TUNEL+ nuclei 24 hrs following induction of AKI. Original magnification ×400. Mean of six animals per group, *P < 0.05 versus TWEAK WT. (C) Active caspase 3 was localized to tubular epithelium 24 hrs following induction of AKI and caspase 3 activation was decreased in TWEAK KO mice. Original magnification ×200. Mean (±S.E.M.) of 4 animals per group. *P < 0.05 versus TWEAK WT. (D) Whole kidney caspase 3 activation 24 hrs following induction of AKI assessed by Western blot of active caspase 3. Representative Western blot and quantification. *P < 0.05 versus TWEAK WT.

Mentions: We next assessed the role of TWEAK on AKI. During AKI an initial wave of cell death is followed by tubular cell proliferation that leads to recovery (Fig. 10A). Renal inflammation is a feature of AKI. In particular, renal expression of mRNA for the inflammatory cytokines TNF-α (11-fold over healthy control, P < 0.05) and IFN-γ (2.5-fold over healthy control, P < 0.05) was increased in AKI induced by a folic acid overdose [15]. TWEAK KO mice had both a decreased early apoptosis peak (Fig. 10B–D), as well as a decreased late cell proliferation peak (Fig. 11A and B). Overall, renal function was better in TWEAK KO mice and there was no impact over functional recovery (Fig. 11C). These data are consistent with the pro-apoptotic action of TWEAK in an inflammatory milieu in cultured tubular cells [15]. Prophylactic treatment with anti-TWEAK antibodies [15] also decreased the rates of tubular cell apoptosis as assessed by TUNEL staining (by 55%, P < 0.05 versus control) and tubular cell proliferation, as assessed by PCNA staining (by 61%, P < 0.05 versus control) (data not shown).


Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia.

Sanz AB, Sanchez-Niño MD, Izquierdo MC, Jakubowski A, Justo P, Blanco-Colio LM, Ruiz-Ortega M, Egido J, Ortiz A - J. Cell. Mol. Med. (2009)

TWEAK neutralization decreases apoptosis in tubular epithelium during acute kidney injury (AKI). AKI is characterized by a local inflammatory milieu (15). (A) Time course of apoptosis, assessed by TUNEL and proliferation assessed as PCNA staining. Peak apoptosis precedes peak proliferation. Mean (±S.E.M.) of six animals per group at each time-point. *P < 0.005 versus control. (B) Apoptotic nuclei were stained by TUNEL. TWEAK deficiency decreases TUNEL+ nuclei 24 hrs following induction of AKI. Original magnification ×400. Mean of six animals per group, *P < 0.05 versus TWEAK WT. (C) Active caspase 3 was localized to tubular epithelium 24 hrs following induction of AKI and caspase 3 activation was decreased in TWEAK KO mice. Original magnification ×200. Mean (±S.E.M.) of 4 animals per group. *P < 0.05 versus TWEAK WT. (D) Whole kidney caspase 3 activation 24 hrs following induction of AKI assessed by Western blot of active caspase 3. Representative Western blot and quantification. *P < 0.05 versus TWEAK WT.
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getmorefigures.php?uid=PMC4516489&req=5

fig10: TWEAK neutralization decreases apoptosis in tubular epithelium during acute kidney injury (AKI). AKI is characterized by a local inflammatory milieu (15). (A) Time course of apoptosis, assessed by TUNEL and proliferation assessed as PCNA staining. Peak apoptosis precedes peak proliferation. Mean (±S.E.M.) of six animals per group at each time-point. *P < 0.005 versus control. (B) Apoptotic nuclei were stained by TUNEL. TWEAK deficiency decreases TUNEL+ nuclei 24 hrs following induction of AKI. Original magnification ×400. Mean of six animals per group, *P < 0.05 versus TWEAK WT. (C) Active caspase 3 was localized to tubular epithelium 24 hrs following induction of AKI and caspase 3 activation was decreased in TWEAK KO mice. Original magnification ×200. Mean (±S.E.M.) of 4 animals per group. *P < 0.05 versus TWEAK WT. (D) Whole kidney caspase 3 activation 24 hrs following induction of AKI assessed by Western blot of active caspase 3. Representative Western blot and quantification. *P < 0.05 versus TWEAK WT.
Mentions: We next assessed the role of TWEAK on AKI. During AKI an initial wave of cell death is followed by tubular cell proliferation that leads to recovery (Fig. 10A). Renal inflammation is a feature of AKI. In particular, renal expression of mRNA for the inflammatory cytokines TNF-α (11-fold over healthy control, P < 0.05) and IFN-γ (2.5-fold over healthy control, P < 0.05) was increased in AKI induced by a folic acid overdose [15]. TWEAK KO mice had both a decreased early apoptosis peak (Fig. 10B–D), as well as a decreased late cell proliferation peak (Fig. 11A and B). Overall, renal function was better in TWEAK KO mice and there was no impact over functional recovery (Fig. 11C). These data are consistent with the pro-apoptotic action of TWEAK in an inflammatory milieu in cultured tubular cells [15]. Prophylactic treatment with anti-TWEAK antibodies [15] also decreased the rates of tubular cell apoptosis as assessed by TUNEL staining (by 55%, P < 0.05 versus control) and tubular cell proliferation, as assessed by PCNA staining (by 61%, P < 0.05 versus control) (data not shown).

Bottom Line: In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function.In conclusion, TWEAK actions in tubular cells are context dependent.This may be relevant for compensatory renal hyperplasia following nephrectomy.

View Article: PubMed Central - PubMed

Affiliation: Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.

ABSTRACT
The tumour necrosis factor (TNF) family member TWEAK activates the Fn14 receptor and has pro-apoptotic, proliferative and pro-inflammatory actions that depend on the cell type and the microenvironment. We explored the proliferative actions of TWEAK on cultured tubular cells and in vivo on renal tubules. Additionally, we studied the role of TWEAK in compensatory proliferation following unilateral nephrectomy and in an inflammatory model of acute kidney injury (AKI) induced by a folic acid overdose. TWEAK increased the proliferation, cell number and cyclin D1 expression of cultured tubular cells, in vitro. Exposure to serum increased TWEAK and Fn14 expression and the proliferative response to TWEAK. TWEAK activated the mitogen-activated protein kinases ERK and p38, the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway and NF-kappaB. TWEAK-induced proliferation was prevented by inhibitors of these protein kinases and by the NF-kappaB inhibitor parthenolide. TWEAK-induced tubular cell proliferation as assessed by PCNA and cyclin D1 expression in the kidneys of adult healthy mice in vivo. By contrast, TWEAK knock-out mice displayed lower tubular cell proliferation in the remnant kidney following unilateral nephrectomy, a non-inflammatory model. This is consistent with TWEAK-induced proliferation on cultured tubular cells in the absence of inflammatory cytokines. Consistent with our previously published data, in the presence of inflammatory cytokines TWEAK promoted apoptosis, not proliferation, of cultured tubular cells. In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function. In conclusion, TWEAK actions in tubular cells are context dependent. In a non-inflammatory milieu TWEAK induces proliferation of tubular epithelium. This may be relevant for compensatory renal hyperplasia following nephrectomy.

Show MeSH
Related in: MedlinePlus