Lithium carbonate attenuates renal expansion but exacerbates cyst morphometry in Pkd1 RC/RC mice

Arginine vasopressin (AVP) promotes epithelial proliferation and fluid secretion primarily by elevating intracellular cyclic AMP (cAMP), amplifying cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan, the only disease-modifying therapy approved for ADPKD, is an antagonist of AVP which directly inhibits this pathway, but its high cost and hepatotoxicity warrant the need for alternative treatments. Because lithium (Li + ) salts have been shown to similarly inhibit AVP-mediated cAMP signaling in tubular epithelium, we hypothesize that Li + may offer a safer and more affordable means to decelerate kidney expansion and cystogenesis. To test this, male (n=24) and female (n=16) Pkd1RC/RC mice aged 10 weeks were divided evenly into groups fed a regular Teklad 2918 diet or Teklad 2918 supplemented with 0.2% lithium carbonate (Li 2 CO 3 ) (w/w) for 8 weeks. To monitor growth of the right kidney noninvasively, we used FujiFilm’s Vevo 3100 system to obtain biweekly ultrasounds; from these, renal volume was estimated by voxel analysis using Fiji/ImageJ. When comparing terminal ultrasound volumes to true kidney mass, we found that ultrasound reliably predicts kidney size in males, (k=0.61, b=51.1, R 2 =0.87) with a somewhat lower predictive value in females (k=0.54, b=54.6, R 2 =0.69). Li + impairs weight gain in both sexes, confounding interpretation of kidney-to-body-weight ratio; Li + also appears to reduce the cross-sectional area of renal histology sections in males (p=0.0040). Endpoint total kidney mass was also lower in males treated with Li + (p=0.0178), but not in females. However, in ultrasound volumetry, Li + was associated with smaller week-0-to-week-8 deltas in kidney size both in males (p=0.0002) and females (p=0.0133). Kim1 and picrosirius red demonstrated histologically that in both sexes tissue injury, interstitial fibrosis, cyst quantity, and cross-sectional cyst area were not affected by Li + ; but cystic index – the proportion of the renal compartment occupied by cystic space – was significantly elevated in males treated with Li + (p=0.0262). In each histological section, we calculated the short-axis Feret diameter (min-FD) of the lumens of multiple arbitrarily selected tubules. Li + yielded a smaller tubular min-FD (p=0.0001) in males but had no effect in females. Li 2 CO 3 ultimately offers no protective benefit to Pkd1RC/RC mice of both sexes. In males, Li 2 CO 3 worsens cystic profile despite reducing total kidney mass. Further histological analysis and immunoblotting will enable better characterization of the role of Li 2 CO 3 in renal injury in Pkd1RC/RC mice of both sexes. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.