Enigmatic Cassandra: renal FGF23 formation in polycystic kidney disease
2014; Elsevier BV; Volume: 85; Issue: 6 Linguagem: Inglês
10.1038/ki.2013.534
ISSN1523-1755
Autores Tópico(s)Biomedical Research and Pathophysiology
ResumoFibroblast growth factor 23 (FGF23) counteracts phosphate excess and tissue calcification. Phosphate intake, Ca2+, parathyroid hormone, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulate FGF23 release from bone. FGF23 inhibits renal 1,25(OH)2D3 formation and phosphate reabsorption. Spichtig and colleagues demonstrate that FGF23 is generated in rodent polycystic kidneys, leading to an increase in plasma FGF23 concentration before reduction in kidney function. FGF23 fails to appreciably downregulate renal phosphate transporter and 1α-25OH-vitamin D hydroxylase activities. Unraveling underlying mechanisms may open diagnostic and therapeutic opportunities. Fibroblast growth factor 23 (FGF23) counteracts phosphate excess and tissue calcification. Phosphate intake, Ca2+, parathyroid hormone, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulate FGF23 release from bone. FGF23 inhibits renal 1,25(OH)2D3 formation and phosphate reabsorption. Spichtig and colleagues demonstrate that FGF23 is generated in rodent polycystic kidneys, leading to an increase in plasma FGF23 concentration before reduction in kidney function. FGF23 fails to appreciably downregulate renal phosphate transporter and 1α-25OH-vitamin D hydroxylase activities. Unraveling underlying mechanisms may open diagnostic and therapeutic opportunities. Fibroblast growth factor 23 (FGF23), a hormone produced mainly in bone and to a lesser extent in the spleen and brain, participates in the regulation of calcium and phosphate metabolism.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar FGF23 decreases the plasma concentration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by downregulating the 1,25(OH)2D3-producing renal 1α-25OH-vitamin D hydroxylase (Cyp27b1) and by upregulating the catabolizing 1,25-hydroxyvitamin D3 24-hydroxylase (Cyp24a1).1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar 1,25(OH)2D3 increases plasma Ca2+ and phosphate concentrations in part by stimulating intestinal absorption and renal reabsorption of calcium and phosphate. Furthermore, FGF23 is itself a powerful direct regulator of renal phosphate transport fostering renal phosphate elimination.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar Thus, FGF23 serves to prevent phosphate overload. For its effects on the kidney, FGF23 requires Klotho.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar Mice lacking functional FGF23 or Klotho suffer from excessive increases in plasma phosphate, calcium, and 1,25(OH)2D3 levels, leading to decrease of bone density, growth retardation, severe vascular calcification, cardiac hypertrophy, osteopenia, emphysema, hypogonadism with infertility, hearing loss, and cognition impairment as well as thymus, fat, and skeletal muscle atrophy.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar The multiple severe disorders result in a dramatic decrease of lifespan.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar The tissue calcification in these mice is not simply the result of CaHPO4 supersaturation but is also driven by stimulation of osteogenic signaling.2.Voelkl J. Alesutan I. Leibrock C.B. et al.Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice.J Clin Invest. 2013; 123: 812-822PubMed Google Scholar FGF23 release is markedly stimulated by 1,25(OH)2D3, and the excessive 1,25(OH)2D3 plasma concentrations in Klotho-deficient mice are followed by an increase in FGF23 plasma levels. Thus, FGF23 release is regulated by negative-feedback loops involving both phosphate and 1,25(OH)2D3 (Figure 1). FGF23 plasma concentrations are similarly elevated in patients suffering from chronic kidney disease (CKD).1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar Notably, plasma FGF23 levels increase before plasma phosphate concentrations and before development of hyperparathyroidism.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar The increase in FGF23 plasma levels may serve to decrease 1,25(OH)2D3 formation in order to curtail intestinal phosphate absorption and thus delay the development of hyperphosphatemia.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar FGF23 plasma concentrations are similarly increased in rats with progressive CKD.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar,3.Hasegawa H. Nagano N. Urakawa I. et al.Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.Kidney Int. 2010; 78: 975-980Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Application of neutralizing FGF23 antibodies in these animals normalizes the plasma 1,25(OH)2D3 levels but by the same token aggravates hyperphosphatemia.3.Hasegawa H. Nagano N. Urakawa I. et al.Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.Kidney Int. 2010; 78: 975-980Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar In contrast to the increased FGF23 plasma concentrations of Klotho-deficient mice, the increase in plasma FGF23 levels in CKD cannot be explained by increased formation of 1,25(OH)2D3, which actually decreases with the progression of CKD. Also in autosomal dominant polycystic kidney disease (ADPKD), which is characterized by the appearance of large renal cysts and reduction of normal functional renal tissue,4.Pavik I. Jaeger P. Ebner L. et al.Soluble klotho and autosomal dominant polycystic kidney disease.Clin J Am Soc Nephrol. 2012; 7: 248-257Crossref PubMed Scopus (58) Google Scholar FGF23 plasma levels are elevated. Plasma FGF23 concentrations increase early, before a clinically relevant decline of renal function.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar ADPKD patients with normal plasma α-Klotho levels were even found to be slightly hypophosphatemic.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar,4.Pavik I. Jaeger P. Ebner L. et al.Soluble klotho and autosomal dominant polycystic kidney disease.Clin J Am Soc Nephrol. 2012; 7: 248-257Crossref PubMed Scopus (58) Google Scholar Spichtig and collaborators5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar (this issue) now report in an elegant study, using two animal models of polycystic kidney disease, the cy/+ Han:SPRD rat and the Pkd1 knockout mouse, that FGF23 expression is dramatically increased in the kidney, but not in bone or spleen. Somewhat surprisingly, at least in rodents, the excessive FGF23 plasma levels associated with polycystic kidney disease appear to result from excessive formation of FGF23 in the cells lining the renal cysts rather than from enhanced FGF23 production in bone.5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar A similar upregulation of renal FGF23 expression may occur in diabetic nephropathy.6.Zanchi C. Locatelli M. Benigni A. et al.Renal expression of FGF23 in progressive renal disease of diabetes and the effect of ACE inhibitor.PLoS One [online]. 2013; 8: e70775Crossref PubMed Scopus (75) Google Scholar In the animal models of the study by Spichtig et al., plasma calcium and phosphate levels, maximal renal tubular phosphate transport, expression and activity of the renal phosphate transporters NaPi-IIa and NaPi-IIc, and renal abundance of Klotho and vitamin D3-metabolizing enzymes remained normal despite a severalfold increase in plasma FGF23 levels and despite enhanced phosphorylation of FGF receptor substrate 2α (Frs2α).5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar This may indicate a state of resistance to the action of FGF23. Even though FGF23 is a powerful stimulator of cardiac hypertrophy,1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar no significant cardiac enlargement was observed.5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Thus, similar to the kidney, the heart may be resistant to the effects of FGF23 in polycystic kidney disease. Moreover, plasma parathyroid hormone levels were increased in these animals,5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar even though FGF23 is expected to inhibit parathyroid hormone secretion.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar Notably elevated plasma FGF23 concentrations were observed prior to evidence for overt impairment of renal function. It remains uncertain, however, whether the seeming lack of FGF23 action was due to resistance of target tissues or some elusive mechanism neutralizing the effects of the hormone. If the lack of effects of FGF23 in rodent polycystic kidney disease5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar results from target tissue resistance, the question arises of which cellular mechanisms may be involved. Moreover, the mechanisms accounting for the upregulation of FGF23 transcription in polycystic kidney disease remain enigmatic. It is tempting to speculate that the upregulation of FGF23 transcript levels is due to FGF23 resistance leading to disruption of a negative-feedback mechanism that normally fine-tunes the local FGF23 abundance. Obvious candidates possibly contributing to the induction of FGF23 synthesis in the kidney are known regulators of FGF23 formation in osteoblasts, including PHEX (phosphate-regulating gene with homology to endopeptidase) and DMP-1 (dentin matrix protein, or cyclin D-binding myb-like protein 1).1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar Loss of function of PHEX or DMP-1 leads to excessive formation of FGF23 in the bone with renal tubular loss of phosphate.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar Intrarenal FGF23 formation is, however, enhanced in cy/+ Han:SPRD rats despite upregulation of the transcription factor Dmp1, which should suppress FGF23 formation.5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar FGF23 formation in osteoblasts is further stimulated by sustained phosphate load even in the absence of hyperphosphatemia; by increased extracellular Ca2+ concentration; by 1,25(OH)2D3 or activation of the vitamin D receptor (VDR); by parathyroid hormone; and by Klotho deficiency.1.Hu M.C. Shiizaki K. Kuro O. et al.Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.Annu Rev Physiol. 2013; 75: 503-533Crossref PubMed Scopus (410) Google Scholar None of these mechanisms explain the FGF23 formation in the kidneys of cy/+ Han:SPRD rats.5.Spichtig D. Zhang H. Mohebbi N. et al.Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.Kidney Int. 2014; 85: 1340-1350Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Other candidates possibly contributing to the stimulation of FGF23 formation or disruption of FGF23 action in renal tissue include signaling pathways that are known to be deranged in polycystic kidney disease—that is, polycystin-1-dependent signaling—such as the growth factor Wnt (Wingless-Int), the Wnt-sensitive transcription factor β-catenin, the transcription factor activator protein 1 (AP-1), phosphoinositide-3-kinase (PI3K), phosphoinositide-dependent protein kinase 1 (PDK1), the PDK1-sensitive protein kinase B/Akt, glycogen synthase kinase 3β (GSK3β), mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 6 (STAT6), the Ca2+-sensitive phosphatase calcineurin, and the calcineurin-sensitive nuclear factor of activated T cells (NFAT).7.Li X. Phosphorylation, protein kinases and ADPKD.Biochim Biophys Acta. 2011; 1812: 1219-1224Crossref PubMed Scopus (8) Google Scholar Polycystin-2 is a Ca2+-permeable cation channel of the transient receptor potential (TRP) family, and thus Ca2+ signaling is deranged in polycystic kidney disease.7.Li X. Phosphorylation, protein kinases and ADPKD.Biochim Biophys Acta. 2011; 1812: 1219-1224Crossref PubMed Scopus (8) Google Scholar At least in theory, de novo FGF23 synthesis in the kidney may result from deranged activity of one or more of these signaling pathways. Candidate signaling pathways possibly contributing to deranged sensitivity to FGF23 include FGF23-sensitive calcineurin–NFAT signaling, which participates in the FGF23-induced cardiac hypertrophy. It would be of particular interest to learn whether calcineurin–NFAT signaling is altered in cardiac tissue of animals or patients suffering from polycystic kidney disease. Finally, candidate signaling molecules possibly contributing to stimulation of renal tubular FGF23 production include Ste20-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase (OSR), as FGF23 serum levels are markedly elevated in mice expressing SPAK8.Pathare G. Foller M. Michael D. et al.Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant Spak.Kidney Blood Press Res. 2012; 36: 355-364Crossref PubMed Scopus (33) Google Scholar or OSR1,9.Pathare G. Foller M. Daryadel A. et al.OSR1-sensitive renal tubular phosphate reabsorption.Kidney Blood Press Res. 2012; 36: 149-161Crossref PubMed Scopus (46) Google Scholar which cannot be activated by WNK (with no lysine). Excessive FGF23 expression in diabetic nephropathy could be reversed by inhibition of angiotensin-converting enzyme.6.Zanchi C. Locatelli M. Benigni A. et al.Renal expression of FGF23 in progressive renal disease of diabetes and the effect of ACE inhibitor.PLoS One [online]. 2013; 8: e70775Crossref PubMed Scopus (75) Google Scholar Whether or not these regulators participate in the observed abnormal synthesis and action of FGF23 in polycystic kidney disease remains to be tested. Whatever the mechanism involved, it may be similarly effective in polycystic kidney disease, diabetic nephropathy, and CKD. Better knowledge of the signaling that accounts for renal FGF23 production and renal resistance to the effects of FGF23 may deepen our understanding of the pathophysiology of polycystic kidney disease, diabetic nephropathy, and CKD in general as well as various additional disorders of mineral metabolism. Moreover, unraveling these mechanisms may open novel therapeutic opportunities in the treatment of those diseases. Ideally, a treatment would take advantage of the positive effects of FGF23 without triggering those effects of FGF23 that are harmful to a given patient. Clearly, tremendous additional experimental effort is needed to uncover the complex interaction between renal disease, FGF23 release and activity, mineral metabolism, vascular calcification, and cardiovascular disorders. The authors are supported by the Deutsche Forschungsgemeinschaft.
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