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Hydrogen sulfide ameliorates aging-associated changes in the kidney

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Abstract

Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H2S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H2S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H2S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18–19 month-old male C57BL/6 mice to receive 30 μmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1β, and IL-6, components of the senescence-associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H2S deficiency. Administration of H2S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis.

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Funding

A Pilot Study Grant to BSK from the Nathan Shock Center of Excellence in Basic Biology of Aging (NIH 1P30-AG013319) supported this work. This work was also supported by grants from the Veterans Affairs Biomedical Laboratory Research and Development Service (I01BX001340 to BSK, 5I01BX000926 to GGC, I01BX002211 to VG, II01BX001641 to RS) and the NIH (DK50190 to GGC, HL113303 to CGK, AG050797 to ABS). DF is supported by the American Heart Association (15GRNT25700363). GGC is a recipient of a Veterans Affairs Senior Research Career Scientist Award (IK6BX003611).

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Authors and Affiliations

  1. Department of Medicine, University of Texas Health San Antonio, 7703, Floyd Curl Drive, MC7882, San Antonio, TX, 78229, USA

    Hak Joo Lee, Denis Feliers, Jeffrey L. Barnes, Sae Oh, Goutam Ghosh Choudhury & Balakuntalam S. Kasinath

  2. South Texas Veterans Health Care System, San Antonio, TX, USA

    Jeffrey L. Barnes, Goutam Ghosh Choudhury, Veronica Galvan, Randy Strong, Adam Salmon & Balakuntalam S. Kasinath

  3. Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, TX, USA

    Vivian Diaz, Veronica Galvan, Randy Strong, James Nelson, Adam Salmon & Balakuntalam S. Kasinath

  4. Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA

    Adam Salmon

  5. Louisiana State University Health Science Center, Shreveport, LA, USA

    Christopher G. Kevil

Authors
  1. Hak Joo Lee
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  2. Denis Feliers
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  3. Jeffrey L. Barnes
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  4. Sae Oh
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  5. Goutam Ghosh Choudhury
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  6. Vivian Diaz
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  7. Veronica Galvan
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  8. Randy Strong
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  9. James Nelson
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  10. Adam Salmon
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  11. Christopher G. Kevil
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  12. Balakuntalam S. Kasinath
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Contributions

BSK, VG, JN, AS, and RS designed the study and analyzed the data. HJL, DF, SO, JB, and CK performed the experiments. All authors participated in data analysis and interpretation. BSK wrote the manuscript; all authors approved it.

Corresponding author

Correspondence to Balakuntalam S. Kasinath.

Ethics declarations

The Institutional Animal Care and Utilization Committee of the University of Texas Health at San Antonio approved the animal studies.

Conflict of interest

CGK has intellectual property for hydrogen sulfide measurement and biomarker and also has equity interest in Innolyzer LLC and Theravasc Inc. J.L.B. is a consultant and co-founder of Probetex, Inc. with ownership interests. All other authors declare that they have no conflict of interest.

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Lee, H.J., Feliers, D., Barnes, J.L. et al. Hydrogen sulfide ameliorates aging-associated changes in the kidney. GeroScience 40, 163–176 (2018). https://doi.org/10.1007/s11357-018-0018-y

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