Vitamin D receptor signaling in podocytes protects against diabetic nephropathy

J Am Soc Nephrol. 2012 Dec;23(12):1977-86. doi: 10.1681/ASN.2012040383. Epub 2012 Nov 2.


Vitamin D and its analogs have antiproteinuric activity and podocytes express the vitamin D receptor, but whether vitamin D signaling in podocytes accounts for this renoprotection is unknown. To investigate this question, we used the 2.5 kb podocin promoter to target Flag-tagged human vitamin D receptor (hVDR) to podocytes in DBA/2J mice. After the induction of diabetes with streptozotocin, transgenic mice had less albuminuria than wild-type controls. In transgenic mice, a low dose of the vitamin D analog doxercalciferol prevented albuminuria, markedly attenuated podocyte loss and apoptosis, and reduced glomerular fibrosis, but it had little effect on the progression of diabetic nephropathy in wild-type mice. Moreover, reconstitution of VDR-null mice with the hVDR transgene in podocytes rescued VDR-null mice from severe diabetes-related renal damage. In culture, 1,25-dihydroxyvitamin D suppressed high-glucose-induced apoptosis of podocytes by blocking p38- and ERK-mediated proapoptotic pathways. Taken together, these data provide strong evidence that vitamin D/VDR signaling in podocytes plays a critical role in the protection of the kidney from diabetic injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Female
  • Humans
  • Hyperglycemia / complications*
  • Hyperglycemia / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred DBA
  • Mice, Knockout
  • Podocytes / metabolism*
  • Pregnancy
  • Promoter Regions, Genetic
  • Receptors, Calcitriol / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • Receptors, Calcitriol