Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion.
Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy.
First Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
Osamu
O
Asai
Kimihiko
K
Nakatani
Tomohiro
T
Tanaka
Hirokazu
H
Sakan
Akihiro
A
Imura
Shuhei
S
Yoshimoto
Ken-ichi
K
Samejima
Yukinari
Y
Yamaguchi
Masaru
M
Matsui
Yasuhiro
Y
Akai
Noboru
N
Konishi
Masayuki
M
Iwano
Yoichi
Y
Nabeshima
Yoshihiko
Y
Saito
D000328:Adult; D000818:Animals; D002118:Calcium / Q000652:urine*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000652:urine; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000652:urine; D015536:Down-Regulation; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D053565:Hypercalciuria / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000652:urine; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
D015220:Calcium Channels; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; C492240:Trpv5 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium