Extra-Large Gα Protein (XLαs) Deficiency Causes Severe Adenine-Induced Renal Injury with Massive FGF23 Elevation.
Fibroblast growth factor-23 (FGF23) is critical for phosphate and vitamin D homeostasis. Cellular and molecular mechanisms underlying FGF23 production remain poorly defined. The extra-large Gα subunit (XLαs) is a variant of the stimulatory G protein alpha-subunit (Gsα), which mediates the stimulatory action of parathyroid hormone in skeletal FGF23 production. XLαs ablation causes diminished FGF23 levels in early postnatal mice. Herein we found that plasma FGF23 levels were comparable in adult XLαs knockout (XLKO) and wild-type littermates. Upon adenine-rich diet-induced renal injury, a model of chronic kidney disease, both mice showed increased levels of plasma FGF23. Unexpectedly, XLKO mice had markedly higher FGF23 levels than WT mice, with higher blood urea nitrogen and more severe tubulopathy. FGF23 mRNA levels increased substantially in bone and bone marrow in both genotypes; however, the levels in bone were markedly higher than in bone marrow. In XLKO mice, a positive linear correlation was observed between plasma FGF23 and bone, but not bone marrow, FGF23 mRNA levels, suggesting that bone, rather than bone marrow, is an important contributor to severely elevated FGF23 levels in this model. Upon folic acid injection, a model of acute kidney injury, XLKO and WT mice exhibited similar degrees of tubulopathy; however, plasma phosphate and FGF23 elevations were modestly blunted in XLKO males, but not in females, compared to WT counterparts. Our findings suggest that XLαs ablation does not substantially alter FGF23 production in adult mice but increases susceptibility to adenine-induced kidney injury, causing severe FGF23 elevations in plasma and bone.
['Matthias|Julia|J|', 'Cui|Qiuxia|Q|', 'Shumate|Lauren T|LT|', 'Plagge|Antonius|A|', 'He|Qing|Q|', 'Bastepe|Murat|M|']
D058186:Acute Kidney Injury D000225:Adenine D000818:Animals D001806:Blood Urea Nitrogen D001842:Bone and Bones D004032:Diet D005260:Female D000089703:Fibroblast Growth Factor-23 D005346:Fibroblast Growth Factors D005492:Folic Acid D019205:GTP-Binding Protein alpha Subunits, Gs D008297:Male D018345:Mice, Knockout D051436:Renal Insufficiency, Chronic D012737:Sex Factors D014803:Vitamin B Complex
fibroblast growth factor-23 stimulatory G protein chronic kidney disease acute kidney injury heterotrimeric G protein