Androgen Receptor Enhances Kidney Stone-CaOx Crystal Formation via Modulation of Oxalate Biosynthesis & Oxidative Stress

Abstract

Males develop kidney stones far more frequently than females with a ratio of 2–3:1, suggesting that androgen receptor (AR) signaling might play a key role in the development of nephrolithiasis. Using the cre-loxP system to selectively knock out AR in glyoxylate-induced calcium oxalate (CaOx) crystal mouse models, we found that the mice lacking hepatic AR had less oxalate biosynthesis, which might lead to lower CaOx crystal formation, and that the mice lacking kidney proximal or distal epithelial AR also had lower CaOx crystal formation. We found that AR could directly up-regulate hepatic glycolate oxidase and kidney epithelial NADPH oxidase subunit p22-PHOX at the transcriptional level. This up-regulation might then increase oxalate biosynthesis and oxidative stress that resulted in induction of kidney tubular injury. Targeting AR with the AR degradation enhancer ASC-J9 led to suppression of CaOx crystal formation via modulation of oxalate biosynthesis and oxidative stress in both in vitro and in vivo studies. Taken together, these results established the roles of AR in CaOx crystal formation.

Prevalence of kidney stones and associated risk factors in the Shunyi District of Beijing

“…Androgen leads to the accumulation of some damaging factors for kidney stone formation, such as calcium, oxalate, and uric acid in urine. 22,23 Men are also more likely to engage in heavy physical labour, to sweat more, and more often be dehydrated. These factors are documented risk factors for kidney stone formation.…”

Effect of Demographics on Excretion of Key Urinary Factors Related to Kidney Stone Risk

“…Studies in rats suggest that testosterone increases and estrogen decreases urinary oxalate excretion(21). A recent study in mice that lack the hepatic androgen receptor (AR) documented reduced oxalate biosynthesis (22), and that mice lacking kidney proximal or distal epithelial AR also had lower CaOx crystal formation. Other in vivo studies found that collagen synthesis was inhibited by estrogen but not affected by testosterone (23).…”

<i>Glechoma longituba</i> (Lamiaceae) alleviates apoptosis in calcium oxalate-induced oxidative stress in kidney proximal tubule epithelial cell line, HK-2

“…CaOx not only obstructs ureters, but also induces reactive oxygen species (ROS), which results in renal cellular injury and inflammation [8,9]. Liang et al have reported that androgen receptor degradation enhancer, ASC-J9, inhibits the formation of CaOx crystals by regulating oxalate biosynthesis and oxidative stress both in vivo and in vitro [10]. In addition, erythrocyte oxidative damage contributes to the tubular damage and stone formation [11].…”