Mutant FGF23 prevents the progression of chronic kidney disease but aggravates renal osteodystrophy in uremic rats.
Phosphorus is one of the important factors that accelerate the progression of chronic kidney disease. Phosphorus restriction or phosphate binders have been reported to have the ability to prevent the progression of chronic kidney disease. FGF23 is a circulating factor that regulates renal phosphorus reabsorption and 1 alpha-hydroxylase activity. We focused on the phosphaturic activity of FGF23 and investigated whether a pharmacological dose of FGF23 is beneficial to the progression of renal insufficiency in uremic rats. To this end, we administered one of the mutant FGF23 expression plasmids into irreversible Thy1 rats. Chronic renal failure rats were established by intravenous injection of anti-rat CD90 (Thy1.1) monoclonal antibody to unilaterally nephrectomized Wistar rats. The rats were then intravenously injected every 2 wk with a naked DNA solution containing 10 microg of MOCK vector or a mutant FGF23 expression plasmid for 13 wk. Renal function was assessed biochemically and histopathologically. Mutant FGF23 significantly decreased serum creatinine and serum urea nitrogen. The marked glomerular sclerosis observed in uremic rats receiving the MOCK vector was ameliorated in rats treated with mutant FGF23. However, mutant FGF23 not only significantly decreased serum 1,25(OH)(2)D and calcium but also aggravated high-turnover renal osteodystrophy from extremely high levels of PTH. These results might be a result of the mechanisms of FGF23 such as phosphaturic activity and lowering the level of 1,25(OH)(2)D. In conclusion, mutant FGF23 prevented the progression of chronic renal failure by regulating serum phosphorus but aggravated renal osteodystrophy from the lowered levels of 1,25(OH)(2)D.
Kusano
Kenichiro
K
Pharmaceutical Research Deptartment I, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. kusanokni@chugai-pharm.co.jp
Saito
Hitoshi
H
Segawa
Hiroko
H
Fukushima
Naoshi
N
Miyamoto
Ken-ichi
K
D000818:Animals; D001806:Blood Urea Nitrogen; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D005269:Femur / Q000187:drug effects / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood*; D051381:Rats / Q000235:genetics; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014511:Uremia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
C505605:Fgf23 protein, rat; D010281:Parathyroid Hormone; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium