Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion

Kidney Int. 2012 Mar;81(6):539-47. doi: 10.1038/ki.2011.423. Epub 2012 Jan 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Calcium / urine*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / urine
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / urine
  • Down-Regulation
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Hypercalciuria / etiology*
  • Hypercalciuria / genetics
  • Hypercalciuria / metabolism
  • Hypercalciuria / urine
  • Kidney Tubules, Distal / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Time Factors
  • Transfection
  • Young Adult


  • Calcium Channels
  • RNA, Messenger
  • Receptors, Cell Surface
  • TRPV Cation Channels
  • TRPV5 protein, human
  • Trpv5 protein, mouse
  • Glucuronidase
  • klotho protein
  • Calcium