Klotho deficiency causes vascular calcification in chronic kidney disease.
Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na(+)-dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885, USA. ming-chang.hu@utsouthwestern.edu
Ming Chang
MC
Hu
Mingjun
M
Shi
Jianning
J
Zhang
Henry
H
Quiñones
Carolyn
C
Griffith
Makoto
M
Kuro-o
Orson W
OW
Moe
D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D005260:Female; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000652:urine; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D010710:Phosphates / Q000378:metabolism; D051381:Rats
D015415:Biomarkers; D010710:Phosphates; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium