Related Experiment Video
Updated: May 1, 2026
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
PKB/SGK-resistant GSK-3 signaling following unilateral ureteral obstruction
Jakob Voelkl1, Sobuj Mia, Adrian Meissner
1Department of Physiology, University of Tübingen, Tübingen, Germany.
Background/Aims:
Renal tissue fibrosis contributes to the development of end-stage renal disease. Causes for renal tissue fibrosis include obstructive nephropathy. The development of renal fibrosis following unilateral ureteral obstruction (UUO) is blunted in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1. Similar to Akt isoforms, SGK1 phosphorylates and thus inactivates glycogen synthase kinase GSK-3. The present study explored whether PKB/SGK-dependent phoshorylation of GSK-3α/β impacts on pro-fibrotic signaling following UUO.
Methods:
UUO was induced in mice carrying a PKB/SGK-resistant GSK-3α/β (gsk-3(KI)) and corresponding wild-type mice (gsk-3(WT)). Three days after the obstructive injury, expression of fibrosis markers in kidney tissues was analyzed by quantitative RT-PCR and western blotting.
Results:
GSK-3α and GSK-3β phosphorylation was absent in both, the non-obstructed and the obstructed kidney tissues from gsk-3(KI) mice but was increased by UUO in kidney tissues from gsk-3(WT) mice. Expression of α-smooth muscle actin, type I collagen and type III collagen in the non-obstructed kidney tissues was not significantly different between gsk-3(KI) mice and gsk-3(WT) mice but was significantly less increased in the obstructed kidney tissues from gsk-3(KI) mice than from gsk-3(WT) mice. After UUO treatment, renal β-catenin protein abundance and renal expression of the β-catenin sensitive genes: c-Myc, Dkk1, Twist and Lef1 were again significantly less increased in kidney tissues from gsk-3(KI) mice than from gsk-3(WT) mice.
Conclusions:
PKB/SGK-dependent phosphorylation of glycogen synthase kinase GSK-3 contributes to the pro-fibrotic signaling leading to renal tissue fibrosis in obstructive nephropathy.
Insights
Serum- and glucocorticoid-inducible kinase (SGK1) signaling promotes kidney fibrosis by phosphorylating glycogen synthase kinase 3 (GSK-3). Blocking this phosphorylation in mice reduced fibrotic markers and pro-fibrotic gene expression following ureteral obstruction.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Signaling
Background:
- Renal tissue fibrosis is a major cause of end-stage renal disease.
- Obstructive nephropathy, such as unilateral ureteral obstruction (UUO), is a significant contributor to renal fibrosis.
- Previous studies showed that UUO-induced renal fibrosis is reduced in mice lacking functional serum- and glucocorticoid-inducible kinase (SGK1).
Purpose of the Study:
- To investigate the role of protein kinase B (PKB)/SGK-dependent phosphorylation of glycogen synthase kinase 3 (GSK-3) in pro-fibrotic signaling.
- To determine if inhibiting GSK-3 phosphorylation impacts fibrotic marker expression and signaling pathways in obstructive nephropathy.
Main Methods:
- Unilateral ureteral obstruction (UUO) was induced in mice with a PKB/SGK-resistant GSK-3α/β (gsk-3(KI)) and wild-type (gsk-3(WT)) littermates.
- Kidney tissues were analyzed three days post-UUO using quantitative RT-PCR and western blotting for fibrosis markers and signaling proteins.
Main Results:
- GSK-3α/β phosphorylation was increased by UUO in wild-type mice but absent in gsk-3(KI) mice.
- Expression of fibrosis markers (α-smooth muscle actin, collagen I, collagen III) was significantly lower in obstructed kidneys of gsk-3(KI) mice compared to gsk-3(WT) mice.
- UUO-induced increases in β-catenin, c-Myc, Dkk1, Twist, and Lef1 were attenuated in gsk-3(KI) mice.
Conclusions:
- PKB/SGK-dependent phosphorylation of GSK-3 is a key mediator of pro-fibrotic signaling in obstructive nephropathy.
- Inhibiting GSK-3 phosphorylation effectively reduces renal fibrosis and associated signaling pathways.
- Targeting the SGK1-GSK3 pathway may offer a therapeutic strategy for preventing or treating renal fibrosis.
