Abstract
Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca2+ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca2+ concentration ([Ca2+]) under elevated pH and/or high [Ca2+] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca2+] measurements reveal that such alkalization not only upsurges Ca2+ influx into PT cells, but the mode of Ca2+ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca2+ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.
Highlights
Renal tubular acidosis (RTA) is characterized by defective renal acid-base regulation due to an inability to excrete hydrogen ions (H+ ) [1]
Our results show that analysis of gene and protein expression of Osteocalcin 2 (OCL2), Osteopontin 4 (OPN-4), and Runt-related transcription factor 2 (RUNX2) were significantly higher in both the WTT and KOT groups when compared to wild type (WT) and KO
We looked at the activation of calcium sensing receptor (CaSR) in this study, since precipitation of calcium phosphate (CaP) are dependent upon the elevation of urinary pH, which is linked to the increased activation of CaSR [47]
Summary
Renal tubular acidosis (RTA) is characterized by defective renal acid-base regulation due to an inability to excrete hydrogen ions (H+ ) [1]. While distal tubular RTA is associated with reduced urinary acid secretion, proximal tubular (PT) RTA results due to impaired bicarbonate (HCO3 − ) reabsorption, ensuing in the decline of serum HCO3 − and alkaline pH at the tubular lumen [2]. Such condition in PT can evoke calcium phosphate (CaP). In hypercalciuric patients with calcium stones, an incomplete renal PT acidosis has been characterized by abnormal bicarbonaturia [4]. If other risk factors such as hypercalciuria are present, the transient bicarbonaturia in these patients promotes favorable conditions to form
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