Calreticulin Shortage Results in Disturbance of Calcium Storage, Mitochondrial Disease, and Kidney Injury.

Renal Ca 2+ reabsorption plays a central role in the fine-tuning of whole-body Ca 2+ homeostasis. Here, we identified calreticulin (Calr) as a missing link in Ca 2+ handling in the kidney and showed that a shortage of Calr results in mitochondrial disease and kidney pathogenesis. We demonstrated that Calr +/- mice displayed a chronic physiological low level of Calr and that this was associated with progressive renal injury manifested in glomerulosclerosis and tubulointerstitial damage. We found that Calr +/- kidney cells suffer from a disturbance in functionally active calcium stores and decrease in Ca 2+ storage capacity. Consequently, the kidney cells displayed an abnormal activation of Ca 2+ signaling and NF-κB pathways, resulting in inflammation and wide progressive kidney injury. Interestingly, the disturbance in the Ca 2+ homeostasis and signaling in Calr +/- kidney mice cells triggered severe mitochondrial disease and aberrant mitophagy, resulting in a high level of oxidative stress and energy shortage. These findings provide novel mechanistic insight into the role of Calr in kidney calcium handling, function, and pathogenesis.