Abstract: SA-OR23
Activation of AMP-Activated Protein Kinase In Vivo Leads to a Polycystic Kidney Disease
Session Information
- Kidneyomics: From Cysts to Populations
October 24, 2020 | Location: Simulive
Abstract Time: 05:00 PM - 07:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Wilson, Laura, University College London Institute of Child Health, London, London, United Kingdom
- Carling, David, MRC London Institute of Medical Sciences, London, Greater London, United Kingdom
Background
Polycystic kidney disease (PKD) is a genetic disorder in which numerous fluid-filled cysts form in the kidney. Despite having identified the causative genes that are mutated in PKD, our understanding of the molecular signalling pathways involved in cystogenesis is limited, hindering PKD drug discovery. In this project, we generated a mouse model of AMP-activated protein kinase (AMPK) activation and observed a polycystic kidney phenotype, reminiscent of PKD. AMPK is known for its role in regulating energy homeostasis and is activated in response to cellular stress. It is currently unknown whether AMPK could play a role in PKD pathogenesis.
Methods
AMPK activation mouse models were generated by expressing the AMPKγ1 isoform with a D316A mutation under the control of β-actin (global) and Ksp (kidney-specific) promoters using the Cre-LoxP system. A constitutively active form of AMPK is produced when AMPKγ1-D316A is incorporated into the enzyme complex. Renal function was assessed using metabolic cages, serum and urine samples were collected for analysis. Kidneys were collected and snap-frozen for biochemical studies or wax-embedded for histological studies.
Results
Global activation of AMPKγ1 resulted in a striking polycystic kidney phenotype. Tubule dilations were evident from 11 days of age, which progressed to heavily cystic kidneys by 3 weeks of age. Adult mice showed signs of polyuria associated with a concentrating defect, polydipsia, kidney damage and compromised renal function. Cysts were observed in the collecting ducts of these mice, consistent with the distal nephron being most heavily afflicted in PKD. Mechanistically, the cystic kidneys had increased cAMP levels and ERK activation (a pathway known to be dysregulated in PKD), increased hexokinase I expression and altered lysosomal protein expression. Kidney-specific activation of AMPKγ1 also produced polycystic kidneys in mice, demonstrating that AMPK activation within the kidney was causative.
Conclusion
These results show that activation of AMPK causes polycystic kidneys to form in mice, raising the possibility that AMPK activation could be a contributing factor in PKD pathogenesis. Dysregulation of the cAMP-ERK pathway in this model suggests a possible mechanism for how AMPK activation could be implicated in renal cystogenesis. Future studies should investigate whether AMPK has a pathogenic role in other PKD models.
Funding
- Private Foundation Support