Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy

Youli Wang, J. Zhou, A. W. Minto, B. K. Hack, J. J. Alexander, M. Haas, Y. C. Li, C. W. Heilig, R. J. Quigg

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The db/db mouse develops features of type II diabetes mellitus as the result of impaired signaling through its abnormal leptin receptor. In spite of accurate metabolic features of diabetes, renal disease manifestations in these mice are not as severe as in humans suggesting the presence of protective genes. There is a growing body of evidence in humans for the relevance of vitamin D in diabetes. Here we followed a large cohort of db/db mice and their non-diabetic db/+ littermates. Transcriptional profiling revealed significant upregulation of 23 genes involved in Ca2+ homeostasis and vitamin D metabolism in db/db glomeruli relative to db/+ glomeruli. Increased glomerular expression of vitamin D3 1α-hydroxylase, vitamin D binding protein, calbindins D9K and D28K, and calcyclin mRNA was confirmed by quantitative reverse transcription-polymerase chain reaction in 20-, 36-, and 52-week-old db/db glomeruli. Although vitamin D3 1α-hydroxylase protein was primarily expressed and upregulated in db/db renal tubules, it was also expressed in glomerular podocytes in vivo. Serum 1,25-dihydroxyvitamin D 3 and urinary Ca2+ excretion were increased >3-fold in db/db mice compared to db/+ mice. Cultured glomerular podocytes had mRNA for vitamin D3 1α-hydroxylase, vitamin D receptor, and calbindin D28K, each of which was increased in high glucose conditions. High glucose also led to enhanced production of fibronectin and collagen IV protein, which was blocked by 1,25-dihydroxyvitamin D3. These results show that vitamin D metabolism is altered in db/db mice leading to metabolic and transcriptional effects. The podocyte is affected by paracrine and potentially autocrine effects of vitamin D, which may explain why db/db mice are resistant to progressive diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)882-891
Number of pages10
JournalKidney International
Volume70
Issue number5
DOIs
Publication statusPublished - Sep 28 2006
Externally publishedYes

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Keywords

  • Calcium
  • Diabetes mellitus
  • Diabetic nephropathy
  • Extracellular matrix
  • Vitamin D

ASJC Scopus subject areas

  • Nephrology

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