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Updated: Jul 9, 2025
A Large Animal Model for Acute Kidney Injury by Temporary Bilateral Renal Artery Occlusion
Published on: February 2, 2021
Abcc6 deficiency prevents rhabdomyolysis-induced acute kidney injury
Audrey Casemayou1,2,3, Julie Belliere1,2,3, Emmanuel Letavernier4,5,6
1Department of Nephrology and Organ Transplantation, Reference Centre for Rare Kidney Diseases (SORARE), French Intensive Care Renal Network (FIRN), University Hospital of Toulouse, 1, Avenue du Pr. Jean Poulhes, 31059, Toulouse Cedex, France.
Abstract:
Rhabdomyolysis is a risk factor for acute kidney injury, transition towards chronic kidney disease, and death. The role of calcium phosphate deposits in the mechanisms of rhabdomyolysis-induced acute kidney injury (RAKI) is still unclear. Better insight of the role calcium in RAKI could lead to new therapeutic avenues. Here, we show in a mice model of RAKI that calcium phosphate deposits were frequent in the kidney (hydroxyapatite) and partly correlated with the severity of the kidney injury. However, the intensity of deposits was highly heterogeneous between mice. Treatment with sodium chloride, sodium bicarbonate or inorganic pyrophosphate (PPi; an inhibitor of the calcium phosphate crystallization), or combinations thereof, did not improve kidney outcomes and hydroxyapatite deposition during RAKI. Unexpectedly, Abcc6 knockout mice (ko), characterized by PPi deficiency, developed less severe RAKI despite similar rhabdomyolysis severity, and had similar hydroxyapatite deposition suggesting alternative mechanisms. This improved kidney outcome at day 2 translated to a trend in improved glomerular filtration rate at month 2 in Abcc6-/-mice and to significantly less interstitial fibrosis. In addition, whereas the pattern of infiltrating cells at day 2 was similar between wt and ko mice, kidneys of Abcc6-/- mice were characterized by more CD19+ B-cells, less CD3+ T-cells and a lower R1/R2 macrophage ratio at month 2. In summary, kidney calcium phosphate deposits are frequent in RAKI but hydration with sodium bicarbonate or sodium chloride does not modify the kidney outcome. Blocking ABCC6 emerges as a new option to prevent RAKI and subsequent transition toward kidney fibrosis.
Insights
Rhabdomyolysis-induced acute kidney injury (RAKI) involves kidney calcium phosphate deposits. Blocking ABCC6, not hydration or pyrophosphate, shows promise in preventing RAKI and fibrosis.
Area of Science:
- Nephrology
- Biochemistry
- Pathology
Background:
- Rhabdomyolysis is a significant risk factor for acute kidney injury (AKI), progression to chronic kidney disease, and mortality.
- The precise role of calcium phosphate deposits in the pathogenesis of rhabdomyolysis-induced AKI (RAKI) remains incompletely understood.
- Elucidating calcium's role in RAKI is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the presence and impact of calcium phosphate deposits in a mouse model of RAKI.
- To evaluate the efficacy of hydration and pyrophosphate (PPi) treatment on kidney outcomes in RAKI.
- To explore the potential protective role of ABCC6 deficiency in RAKI and its long-term consequences.
Main Methods:
- Induction of RAKI in a mouse model.
- Assessment of kidney hydroxyapatite deposition and injury severity.
- Administration of sodium chloride, sodium bicarbonate, or inorganic pyrophosphate (PPi).
- Comparison of kidney outcomes and cellular infiltration in wild-type and Abcc6 knockout mice.
Main Results:
- Frequent kidney hydroxyapatite deposits were observed in RAKI, with variable intensity.
- Treatments with sodium chloride, sodium bicarbonate, or PPi did not improve kidney outcomes or reduce hydroxyapatite deposition.
- Abcc6 knockout mice exhibited less severe RAKI and reduced interstitial fibrosis, despite similar rhabdomyolysis severity.
- Abcc6 knockout mice showed distinct immune cell profiles in the kidney at later time points, including increased B-cells and altered macrophage ratios.
Conclusions:
- Kidney calcium phosphate deposits are common in RAKI, but hydration and PPi are ineffective treatments.
- Blocking ABCC6 represents a potential therapeutic approach to mitigate RAKI and prevent subsequent kidney fibrosis.
- Abcc6 deficiency confers protection against RAKI, suggesting alternative protective mechanisms beyond direct inhibition of calcium phosphate deposition.
