Dataset Information

Impact of AMP-Activated Protein Kinase ?1 Deficiency on Tissue Injury following Unilateral Ureteral Obstruction.

ABSTRACT:

Background

AMP-activated protein kinase (Ampk) is a sensor of the cellular energy status and a powerful regulator of metabolism. Activation of Ampk was previously shown to participate in monocyte-to-fibroblast transition and matrix protein production in renal tissue. Thus, the present study explored whether the catalytic Ampk?1 isoform participates in the regulation of the renal fibrotic response following unilateral ureteral obstruction (UUO).

Methods

UUO was induced in gene-targeted mice lacking functional Ampk?1 (Ampk?1-/-) and in corresponding wild-type mice (Ampk?1+/+). In the obstructed kidney and, for comparison, in the non-obstructed control kidney, quantitative RT-PCR, Western blotting and immunostaining were employed to determine transcript levels and protein abundance, respectively.

Results

In Ampk?1+/+ mice, UUO significantly up-regulated the protein abundance of the Ampk?1 isoform, but significantly down-regulated the Ampk?2 isoform in renal tissue. Phosphorylated Ampk? protein levels were significantly increased in obstructed kidney tissue of Ampk?1+/+ mice but not of Ampk?1-/- mice. Renal expression of ?-smooth muscle actin was increased following UUO, an effect again less pronounced in Ampk?1-/- mice than in Ampk?1+/+ mice. Histological analysis did not reveal a profound effect of Ampk?1 deficiency on collagen 1 protein deposition. UUO significantly increased phosphorylated and total Tgf-ß-activated kinase 1 (Tak1) protein, as well as transcript levels of Tak1-downstream targets c-Fos, Il6, Pai1 and Snai1 in Ampk?1+/+ mice, effects again significantly ameliorated in Ampk?1-/- mice. Moreover, Ampk?1 deficiency inhibited the UUO-induced mRNA expression of Cd206, a marker of M2 macrophages and of Cxcl16, a pro-fibrotic chemokine associated with myeloid fibroblast formation. The effects of Ampk?1 deficiency during UUO were, however, paralleled by increased tubular injury and apoptosis.

Conclusions

Renal obstruction induces an isoform shift from Ampk?2 towards Ampk?1, which contributes to the signaling involved in cell survival and fibrosis.

SUBMITTER: Mia S

PROVIDER: S-EPMC4540418 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Impact of AMP-Activated Protein Kinase α1 Deficiency on Tissue Injury following Unilateral Ureteral Obstruction.

Mia Sobuj S Federico Giuseppina G Feger Martina M Pakladok Tatsiana T Meissner Adrian A Voelkl Jakob J Groene Hermann-Josef HJ Alesutan Ioana I Lang Florian F

PloS one 20150818 8

<h4>Background</h4>AMP-activated protein kinase (Ampk) is a sensor of the cellular energy status and a powerful regulator of metabolism. Activation of Ampk was previously shown to participate in monocyte-to-fibroblast transition and matrix protein production in renal tissue. Thus, the present study explored whether the catalytic Ampkα1 isoform participates in the regulation of the renal fibrotic response following unilateral ureteral obstruction (UUO).<h4>Methods</h4>UUO was induced in gene-targ ...[more]

PMID: 26285014

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