Renal ischemia-reperfusion injury impairs renal calcium, magnesium, and phosphate handling in mice

Fibroblast growth factor 23 (FGF23) levels are elevated in patients with acute kidney injury (AKI). The consequences on renal Ca2+, Mg2+, and P-i regulatory mechanisms are unknown. We hypothesized that renal ischemia-reperfusion (I/R) injury alters the expression of important renal Ca2+, Mg2+, and P-i transport proteins. I/R injury was induced in male C57BL/6 mice by clamping both renal arteries for 27min. Mice were investigated 18h later. The mRNA and protein levels of renal Ca2+, Mg2+, and P-i transport proteins were measured by RT-qPCR and western blot analysis. I/R injury-induced hyperphosphatemia and hypermagnesemia were paralleled by a decrease in glomerular filtration rate and an increase in the fractional excretion of Ca2+, Mg2+, and P-i. I/R injury affected the fibroblast growth factor 23 (FGF23)-klotho-vitamin D axis by increasing plasma levels of FGF23 and downregulation of renal klotho expression. Plasma levels of PTH and 1,25-dihydroxyvitamin D-3 were unchanged. Further, downregulation of key genes for paracellular reabsorption of Ca2+ and Mg2+ (claudin (Cldn)2, Cldn10b, Cldn16, Cldn19) and for active transcellular transport of Ca2+, Mg2+, and P-i (calbindin-D-28K, Ncx1, Pmca4, Cnnm2, Trpm7, NaPi-2a, and NaPi-2c) was observed. However, renal expression of Trpv5 and Trpv6 was increased. In vitro studies support a direct effect of proinflammatory cytokines on the mRNA expression of Cldn16, Cldn19, and Trpv6. Our findings indicate that renal I/R injury increases FGF23 blood levels independent of PTH and 1,25-dihydroxyvitamin D-3. This increase is associated with hypermagnesemia, hyperphosphatemia, and increased or decreased expression of specific renal Ca2+, Mg2+, and P-i transporters, respectively.