1. ¹Department of Medicine, The University of Chicago, Chicago, Illinois, USA
2. ²Department of Pathology, Johns Hopkins Medical Institute, Baltimore, Maryland, USA

Correspondence: RJ Quigg, Section of Nephrology, The University of Chicago, 5841 S. Maryland Ave., MC5100, Chicago, Illinois 60637, USA. E-mail: rquigg@uchicago.edu

Received 31 October 2005; Revised 12 April 2006; Accepted 18 April 2006; Published online 5 July 2006.

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 1-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 1-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 D₃ and urinary Ca²⁺ excretion were increased >3-fold in db/db mice compared to db/+ mice. Cultured glomerular podocytes had mRNA for vitamin D₃ 1-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.