miR-148b-5p regulates hypercalciuria and calcium-containing nephrolithiasis

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Calcium-containing kidney stones are common but their pathogenesis is unclear.
• Idiopathic hypercalciuria is a frequent risk factor for kidney calculi.
• Urinary exosomal microRNAs offer a non-invasive method for renal tissue analysis.

Purpose of the Study:

• To investigate the role of urinary exosomal microRNAs in calcium kidney stone formation.
• To identify molecular mechanisms underlying idiopathic hypercalciuria and nephrolithiasis.
• To explore potential therapeutic targets for calcium nephrolithiasis.

Main Methods:

• Analysis of urinary exosomal microRNAs in kidney stone patients.
• In vivo studies using rat models with systemic miR-148b-5p administration and inhibition.
• RNA immunoprecipitation and deep sequencing to identify miR-148b-5p targets.
• Generation of mice deficient in calcitonin receptor (Calcr) in distal epithelial cells.
• Investigation of the circRNA-83536/miR-24-3p/Calcr signaling pathway.
• Validation using human kidney tissue samples.

Main Results:

• Elevated miR-148b-5p levels were detected in exosomes from kidney stone patients.
• miR-148b-5p administration increased urinary calcium excretion and stone formation in rats.
• miR-148b-5p directly suppresses Calcr expression.
• Calcr deficiency in mice led to increased urinary calcium excretion and renal calcification.
• The circRNA-83536/miR-24-3p pathway mediates miR-148b-5p's regulation of Calcr.

Conclusions:

• miR-148b-5p promotes calcium kidney stone formation by downregulating Calcr via the circRNA-83536/miR-24-3p axis.
• This pathway represents a novel mechanism in the pathogenesis of calcium nephrolithiasis.
• Targeting the miR-148b-5p/circRNA-83536/miR-24-3p/Calcr axis may offer new therapeutic strategies for kidney stones.