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.