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Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice

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Abstract

Semaphorin 3A (sema3A) was recently identified as an early diagnostic biomarker of acute kidney injury. However, its role as a biomarker and/or mediator of chronic kidney disease (CKD) related to diabetic nephropathy is unknown. We examined the expression of sema3A in diabetic animal models and in humans and tested whether sema3A plays a pathogenic role in the development of diabetic nephropathy. The expression of sema3A was localized to podocytes and epithelial cells in distal tubules and collecting ducts in control animals, and its expression was increased following the induction of diabetes. Quantification of sema3A urinary excretion in three different diabetic mouse models showed that excretion was increased as early as 2 weeks after the induction of diabetes and increased over time, in conjunction with the development of nephropathy. Consistent with the mouse data, increased sema3A urinary excretion was detected in diabetic patients with albuminuria, particularly in those with macroalbuminuria. Genetic ablation of sema3A or pharmacological inhibition with a novel sema3A inhibitory peptide was protected against diabetes-induced albuminuria, kidney fibrosis, inflammation, oxidative stress, and renal dysfunction. We conclude that sema3A is both a biomarker and a mediator of diabetic kidney disease and could be a promising therapeutic target in diabetic nephropathy.

Key messages

  • Diabetes induced sema3A excretion in urine.

  • Increased semaphorin 3A was associated with severity of albuminuria.

  • Seme3A-mediated diabetes induced glomerulosclerosis.

  • Peptide-based inhibition of semaphorin3A suppressed diabetic nephropathy.

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Author contributions

RM and PR researched the data and wrote the manuscript. CJ researched the data and reviewed and edited the manuscript. FN researched the data and reviewed and edited the manuscript. RTN reviewed and edited the manuscript. MB and NLW reviewed and edited the manuscript. GR wrote manuscript and edited the manuscript.

Funding

This work was supported by an R01grant (1R01DK083379-01A6) to Ganesan Ramesh from NIH-NIDDK. PR and RM are recipients of American Heart Association Postdoctoral fellowship.

Conflict of interest statement

The results presented in this paper have not been published previously in whole or part. All authors declared that they have no conflict of interest related to this study.

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Authors and Affiliations

  1. Department of Medicine, Vascular Biology Center, Georgia Regents University, CB-3702, 1459 Laney-Walker Blvd, Augusta, GA, 30912, USA

    Riyaz Mohamed, Punithavathi Ranganathan, Calpurnia Jayakumar, Neal L. Weintraub & Ganesan Ramesh

  2. Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Ferdau L. Nauta & Ron T. Gansevoort

  3. Department of Physiology, Georgia Regents University, Augusta, GA, 30912, USA

    Michael Brands

Authors
  1. Riyaz Mohamed
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  2. Punithavathi Ranganathan
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  3. Calpurnia Jayakumar
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  4. Ferdau L. Nauta
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  5. Ron T. Gansevoort
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  6. Neal L. Weintraub
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  7. Michael Brands
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  8. Ganesan Ramesh
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Corresponding author

Correspondence to Ganesan Ramesh.

Additional information

Riyaz Mohamed and Punithavathi Ranganathan equally contributed to this work.

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Mohamed, R., Ranganathan, P., Jayakumar, C. et al. Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice. J Mol Med 92, 1245–1256 (2014). https://doi.org/10.1007/s00109-014-1209-3

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  • DOI: https://doi.org/10.1007/s00109-014-1209-3

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