LIM kinase function and renal growth: potential role for LIM kinases in fetal programming of kidney development

Sparrow, Alexander J.; Sweetman, Dylan; Welham, Simon J.M.

Abstract

Aims

Maternal dietary restriction during pregnancy impairs nephron development and results in offspring with fewer nephrons. Cell turnover in the early developing kidney is altered by exposure to maternal dietary restriction and may be regulated by the LIM-kinase family of enzymes. We set out to establish whether disturbance of LIM-kinase activity might play a role in the impairment of nephron formation.

Main methods

E12.5 metanephric kidneys and HK2 cells were grown in culture with the pharmacological LIM-kinase inhibitor BMS5. Organs were injected with DiI, imaged and cell numbers measured over 48 h to assess growth. Cells undergoing mitosis were visualised by pH 3 labelling.

Key findings

Growth of cultured kidneys reduced to 83% of controls after exposure to BMS5 and final cell number to 25% of control levels after 48 h. Whilst control and BMS5 treated organs showed cells undergoing mitosis (100 ± 11 cells/field vs 113 ± 18 cells/field respectively) the proportion in anaphase was considerably diminished with BMS5 treatment (7.8 ± 0.8% vs 0.8 ± 0.6% respectively; P < 0.01). This was consistent with effects on HK2 cells highlighting a severe impact of BMS5 on formation of the mitotic spindle and centriole positioning. DiI labelled cells migrated in 100% of control cultures vs 0% BMS5 treated organs. The number of nephrogenic precursor cells appeared depleted in whole organs and formation of new nephrons was blocked by exposure to BMS5.

Significance

Pharmacological blockade of LIM-kinase function in the early developing kidney results in failure of renal development. This is likely due to prevention of dividing cells from completion of mitosis with their resultant loss.

Citation

Sparrow, A. J., Sweetman, D., & Welham, S. J. (2017). LIM kinase function and renal growth: potential role for LIM kinases in fetal programming of kidney development. Life Sciences, 186, 17-24. https://doi.org/10.1016/j.lfs.2017.07.034

• Journal Article Type: Article
• Acceptance Date: Jul 30, 2017
• Online Publication Date: Aug 1, 2017
• Publication Date: 2017-10
• Deposit Date: Aug 4, 2017
• Publicly Available Date: Aug 2, 2018
• Journal: Life Sciences
• Print ISSN: 0024-3205
• Electronic ISSN: 1879-0631
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 186
• Pages: 17-24
• DOI: https://doi.org/10.1016/j.lfs.2017.07.034
• Keywords: Kidney; Nephrogenesis; Cofilin1; Limk1; Limk2; Mitosis; Programming
• Public URL: https://nottingham-repository.worktribe.com/output/876062
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S0024320517303739
• Additional Information: This article is maintained by: Elsevier; Article Title: LIM kinase function and renal growth: Potential role for LIM kinases in fetal programming of kidney development; Journal Title: Life Sciences; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.lfs.2017.07.034; Content Type: article; Copyright: © 2017 Elsevier Inc. All rights reserved.
• Contract Date: Aug 4, 2017