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

Renal Ca reabsorption plays a central role in the fine-tuning of whole-body Ca homeostasis. Here, we identified calreticulin (Calr) as a missing link in Ca 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 storage capacity. Consequently, the kidney cells displayed an abnormal activation of Ca signaling and NF-κB pathways, resulting in inflammation and wide progressive kidney injury. Interestingly, the disturbance in the Ca 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.