Partial Answers from Partial Klotho Deficiency

Abstract

Membrane-bound Klotho is the coreceptor for fibroblast growth factor 23 (FGF23) that increases its affinity for FGF receptors (FGFRs). 1 Binding of FGF23 to FGFR-Klotho complexes in the kidney stimulates phosphaturia and inhibits production of 1,25-dihydroxyvitamin D. 2 In the parathyroid glands, FGF23-FGFR-Klotho signaling also inhibits parathyroid hormone (PTH) secretion. 3 Alternative splicing or cleavage of the extracellular domain of Klotho yields a soluble form of the protein, which possesses phosphaturic effects and also activates calcium reabsorption by transient receptor potential vanilloid 5 in the distal nephron. 4 Landmark studies of genetically altered mice helped illuminate the interdependent roles of Klotho and FGF23 in calcium and phosphate homeostasis. Klotho-ablated (kl/kl) mice develop severe hyperphosphatemia, markedly elevated levels of FGF23, endogenous 1,25-dihydroxyvitamin D intoxication with resultant hypercalcemia, suppressed levels of PTH, and hypercalciuria. [4][5][6] The animals also manifest accelerated aging that can be prevented by a low phosphate diet or ablation of CYP27B1, which ameliorate the biochemical alterations. 7,8 These data suggest that disordered mineral metabolism contributes directly to shortened lifespan of kl/kl mice. Recent reports of direct adverse effects of Klotho deficiency on the vasculature and FGF23 excess on the myocardium suggest that these factors may also play a contributory pathophysiological role in the premature death associated with Klotho deficiency. 9,10 The study by Olauson et al. in this issue of JASN 11 sheds new light on this rapidly evolving field. The investigators genetically engineered mice with partial Klotho deletion limited to the distal tubule (Ksp-Kl 2/2 ), which is the predominant site of renal Klotho expression, in order to define the contribution of kidney-specific Klotho deficiency to the abnormalities observed in published reports of kl/kl. As expected, the variable degree of renal Klotho deletion introduced much more phenotypic variability than in complete knockout models but also allowed an evaluation of dose-response relationships between Klotho expression levels and biochemical phenotype. Unlike kl/kl, Ksp/Kl 2/2 mice demonstrate a normal gross phenotype, preserved fertility, no vascular calcification, and normal renal parenchyma devoid of the intrarenal calcifications and interstitial fibrosis that develop in kl/kl mice. From a biochemical perspective, partial Klotho deletion is associated with hyperphosphatemia, elevated FGF23 levels, and reduced PTH, but serum calcium and 1,25-dihydroxyvitamin D levels were not significantly different compared with wildtype animals.Many of these results recapitulate previously reported findings from kl/kl, albeit in milder form, which is consistent with the partial knockout. However, critical distinctions between partial and complete Klotho ablation reveal additional important nuances of the feedback loops that regulate mineral metabolism and their potential effects on the cardiovascular ...