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Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy
1Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
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 1alpha-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 1alpha-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 1alpha-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.
Insights
Vitamin D metabolism is altered in diabetic mice (db/db), with increased vitamin D activity in the kidneys. This may protect against diabetic kidney disease by influencing podocyte function.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Type II diabetes mellitus in db/db mice exhibits metabolic features but less severe renal disease than in humans.
- Evidence suggests a role for vitamin D in human diabetes.
- Investigating vitamin D's role in diabetic nephropathy in db/db mice is crucial.
Purpose of the Study:
- To investigate alterations in vitamin D metabolism and homeostasis in the kidneys of db/db mice.
- To determine the effect of high glucose on vitamin D-related gene expression and protein production in cultured podocytes.
- To explore the potential protective role of vitamin D in diabetic nephropathy.
Main Methods:
- Transcriptional profiling of glomeruli from db/db mice and non-diabetic db/+ littermates.
- Quantitative reverse transcription-polymerase chain reaction (RT-PCR) to confirm gene expression.
- Immunohistochemistry to assess protein localization.
- Measurement of serum vitamin D metabolites and urinary calcium excretion.
- In vitro studies using cultured glomerular podocytes exposed to high glucose.
Main Results:
- db/db mice showed significant upregulation of genes involved in calcium (Ca2+) homeostasis and vitamin D metabolism in glomeruli.
- Increased glomerular expression of key vitamin D pathway genes (e.g., vitamin D3 1alpha-hydroxylase, vitamin D binding protein, calbindins) was confirmed.
- Elevated serum 1,25-dihydroxyvitamin D3 and urinary Ca2+ excretion were observed in db/db mice.
- High glucose increased fibronectin and collagen IV production in cultured podocytes, an effect blocked by 1,25-dihydroxyvitamin D3.
- Vitamin D3 1alpha-hydroxylase was expressed in glomerular podocytes and upregulated in renal tubules of db/db mice.
Conclusions:
- Vitamin D metabolism is significantly altered in db/db mice, with increased activity in the kidneys.
- The podocyte is a target for vitamin D, potentially via paracrine and autocrine mechanisms.
- Vitamin D may play a protective role against progressive diabetic nephropathy in db/db mice, explaining their resistance.
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