Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney

Takao, Masaki; Foti, Rita; Hill, Prudence A.; Ikezumi, Yohei; Atkins, Robert C.; Nikolic-Paterson, David J.

doi:10.1046/j.1523-1755.2003.00874.x

Cited by 95 publications

(101 citation statements)

References 21 publications

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“…UUO, a well characterized mouse model of renal fibrosis, was performed under general anesthesia as previously described. 36 Mice were killed on day1, day 3, or day 7 after UUO and renal tissues were harvested.…”

Section: Animalsmentioning

confidence: 99%

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

Sasaki

Doi

Nakashima

et al. 2016

Journal of the American Society of Nephrology

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TGF-b1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-b1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-b1 neutralizing antibody. TGF-b1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P,0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-b1-induced a-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.

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Section: Animalsmentioning

confidence: 99%

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

Sasaki

Doi

Nakashima

et al. 2016

Journal of the American Society of Nephrology

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“…Immunoperoxidase staining for phosphorylated JNK (p-JNK), c-Jun, p-c-Jun Ser63, p-c-Jun Ser73, p-ERK, and AQP2 was performed on 4-m sections of formalin-fixed tissue using antigen retrieval (microwave oven heating in 0.1 M sodium citrate [pH 6.0] for 10 min) followed by a three-layer avidin-biotin peroxidase complex (ABC) staining method (27). Immunoperoxidase staining for cleaved caspase-3 and ED1 ϩ macrophages was performed on formalin-fixed tissue sections without antigen retrieval and using a three-layer PAP staining method.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Immunoperoxidase staining for ␣-SMA used a three-layer PAP method on methylcarn-fixed tissue, and immunostaining for collagen IV used frozen sections with the avidin-biotin peroxidase complex method. Two-color immunostaining for AQP2 and p-JNK used formalin-fixed tissue sections as described previously (27).…”

Section: Immunohistochemistrymentioning

confidence: 99%

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

Ma¹,

Flanc²,

Tesch³

et al. 2007

Journal of the American Society of Nephrology

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157

139

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Renal fibrosis and tubular apoptosis are common mechanisms of progressive kidney disease. In vitro studies have implicated the c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal fibrosis and tubular apoptosis in the unilateral ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK isoforms, CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2 isoforms. Administration of CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal fibrosis in terms of interstitial myofibroblast accumulation and collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules TGF-␤1 and connective tissue growth factor. CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal fibrosis in the unilateral ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive kidney disease.

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“…Interestingly, immunohistochemical studies have recently revealed that the phosphorylated active form of ERK1/2 (pERK1/2) is expressed at detectable basal levels in the distal (but not in the proximal) nephron of normal rat kidney in vivo (14 -17). In the collecting duct Masaki et al (16) have recently shown that pERK1/2 is expressed in the principal cell and not in the intercalated cells. These in vivo data suggest that basal activity of ERK1/2 may have a specific physiological relevance in the principal cell of the collecting duct, independent of hormonal or ligand-induced stimuli and distinct from the hormonedependent effects observed in intercalated cells.…”

mentioning

confidence: 99%

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Michlig

Mercier

Doucet

et al. 2004

Journal of Biological Chemistry

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The collecting duct of normal kidney exhibits significant activity of the MEK1/2-ERK1/2 pathway as shown in vivo by immunostaining of phosphorylated active ERK1/2 (pERK1/2). The MEK1/2-ERK1/2 pathway controls many different ion transports both in proximal and distal nephron, raising the question of whether this pathway is involved in the basal and/or hormone-dependent transepithelial sodium reabsorption in the principal cell of the cortical collecting duct (CCD), a process mediated by the apical epithelial sodium channel and the basolateral sodium pump (Na,K-ATPase). To answer this question we used ex vivo microdissected CCDs from normal mouse kidney or in vitro cultured mpkCCD cl4 principal cells. Significant basal levels of pERK1/2 were observed ex vivo and in vitro. Aldosterone and vasopressin, known to up-regulate sodium reabsorption in CCDs, did not change ERK1/2 activity either ex vivo or in vitro. Basal and aldosterone-or vasopressin-stimulated sodium transport was down-regulated by the MEK1/2 inhibitor PD98059, in parallel with a decrease in pERK1/2 in vitro. The activity of Na,K-ATPase but not that of epithelial sodium channel was inhibited by MEK1/2 inhibitors in both unstimulated and aldosterone-or vasopressin-stimulated CCDs in vitro. Cell surface biotinylation showed that intrinsic activity rather than cell surface expression of Na,K-ATPase was controlled by pERK1/2. PD98059 also significantly inhibited the activity of Na,K-ATPase ex vivo. Our data demonstrate that the ERK1/2 pathway controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell and indicate that basal constitutive activity of the ERK1/2 pathway is a critical component of this control.The extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) 1 pathway, also known as p42 and p44 mitogen-activated protein (MAP) kinase pathway, plays a critical role in cellular responses to a wide variety of external stimuli including hormones, growth factors, and environmental stress (for review, see Refs. 1 and 2). The ERK1/2 pathway is a three-step kinase cascade in which ERK1/2 kinases are phosphorylated/ activated by two immediate upstream MAP kinases (MEK1 and MEK2 (MEK1/2)) that are in turn phosphorylated/activated by several MAP kinases (i.e. MOS, C-Raf, and B-Raf). Activated ERK1/2 (pERK1/2) phosphorylates various downstream effectors involved in differentiation, proliferation, apoptosis, survival, cellular metabolism, and ion transport. The MAP kinase cascade may also be constitutively activated independent of external stimuli or ligands. This basal activity is the result of the balance between positive and negative factors regulating MAP kinases activity; that is, phosphatases, subcellular localization, expression of scaffold proteins, and activity of other kinases. In the kidney, the ERK1/2 pathway is involved in the hormonal regulation of different apical and basolateral channels or transporters expressed along the nephron for maintaining the extracellular fluid homeostasis. In the proximal tubule the ERK...

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Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney

Cited by 95 publications

References 21 publications

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

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