MiR-148b-5p promotes hypercalciuric kidney stone formation via regulating circRNA-83536/miR-24-3p/Calcitonin Receptor signaling [RIP-seq]

Calcium-containing stones are the most prevalent type of kidney stones. Idiopathic hypercalciuria is one of the most common metabolic disturbances in calcium stone-forming patients. However, the mechanism of idiopathic hypercalciuria is unclear. We profiled urinary exosomal miRNAs between normal and kidney stone patients as a proxy of kidney tissues to identify mechanistic basis underlying kidney stone formation. We found that miR-148b-5p was notably increased in urinary exosomes from kidney stone patients compared to healthy controls. Systemic delivery of miR-148b-5p agomir increases urinary calcium excretion, and systemic delivery of miR-148b-5p antagomir suppresses kidney stone formation via reducing urinary calcium excretion in rats. Using Argonaute 2 (Ago2) RNA immunoprecipitation followed by deep sequencing, we found miR-148b-5p can promote urinary calcium excretion and kidney stone formation via suppressing Calcitonin Receptor (Calcr) expression. Furthermore, mice lacking distal epithelial Calcr had higher urinary calcium excretion and renal papillary calcification after co-administration of vitamin D and calcium intake. Mechanism dissection suggested that miR-148b-5p can suppress Calcr expression via regulating circRNA-83536/miR-24-3p signaling. Significantly these mechanistic findings were confirmed in human kidney tissues, suggesting similar mechanistic relationships exist in humans. Together, these results demonstrate that miR-148b-5p can promote urinary calcium excretion and calcium-containing kidney stone formation via circRNA-83536/miR-24-3p/Calcr signals, and targeting this newly identified pathway may help to develop new therapies to better suppress calcium-containing kidney stone formation and recurrence.