Renal Ca2+ reabsorption plays a central role in the fine-tuning of whole-body Ca2+ homeostasis. Here, we identified calreticulin (Calr) as a missing link in Ca2+ 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 Ca2+ storage capacity. Consequently, the kidney cells displayed an abnormal activation of Ca2+ signaling and NF-κB pathways, resulting in inflammation and wide progressive kidney injury. Interestingly, the disturbance in the Ca2+ 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.
Keywords: autophagy; calcium signaling; calcium storage; calreticulin; kidney fibrosis; mitochondrial disease; oxidative stress.