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AMPK is dispensable for physiological podocyte and glomerular functions but prevents glomerular fibrosis in experimental diabetes
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  • Published: 28 March 2026

AMPK is dispensable for physiological podocyte and glomerular functions but prevents glomerular fibrosis in experimental diabetes

  • Swayam Prakash Srivastava  ORCID: orcid.org/0000-0002-7162-30911,
  • Olivia Kopasz-Gemmen1,
  • Abhiram Kunamneni1,
  • Aaron Thurman1,
  • Shota Yoshida1,
  • Eden Ozkan1,
  • Vinamra Swaroop1,
  • Rahul Nanwani1,
  • Ajan Arora1,
  • Arya Joshi1,
  • Om Khuperkar1,
  • Mariam Hamed1,
  • Mihir Suresh Bharadwaj1,
  • Niloy Islam1,
  • Adesh Urval1,
  • Junying Wang1,
  • Sungki Hong1,
  • Keizo Kanasaki2,
  • Daisuke Koya2 &
  • …
  • Ken Inoki  ORCID: orcid.org/0000-0001-8882-444X1,3,4 

Cell Death Discovery , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Nephrosclerosis
  • Renal fibrosis

Abstract

AMP-activated protein kinase (AMPK) has been postulated to be crucial in regulating various renal physiology and pathophysiology processes, including energy metabolism, ion and water transport, inflammation, and hypertrophy. However, the specific roles of AMPK in podocytes, cells critical for maintaining glomerular filtration, have not been fully explored using genetic model animals. In this study, we generated mice lacking both AMPK α1 and α2 catalytic subunits in glomerular podocytes (pmut). Our findings revealed that, surprisingly, AMPK is dispensable for normal podocyte function. These knockout mice could live as long as their wild-type littermates without showing any pathological alterations in their glomeruli or glomerular function at two years of age. However, under diabetic conditions, the diabetic pmut mice exhibited increased lipid and collagen accumulation and an elevated expression of mesenchymal proteins in their glomeruli. They also showed more significant albuminuria compared to control diabetic mice. Under high-glucose culture conditions, glomeruli isolated from pmut mice showed reduced expression of mitochondrial genes (e.g., Ndufv2) and increased leakage of mitochondrial components. Additionally, there was increased expression of genes associated with nucleotide-sensing and pro-inflammatory pathways (including mb21d2, IL-1β, and NF-κB). These observations suggest that while AMPK is not necessary for podocyte function in healthy kidneys, it is crucial for preventing glomerular fibrosis resulting from lipotoxicity and inflammation under diabetic conditions.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author (Swayam Prakash Srivastava; spsr@umich.edu) upon request.

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Acknowledgements

We thank Dr. Sean Morrison for sharing Ampk α1 fl/flα2 fl/fl mice (B6) [110] and Dr. Frank III Brosius for podocin-Cre (B6) mice [117, 118].

Funding

This study was supported by grants from the NIH (DK124709 and GM145631).

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Authors and Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Swayam Prakash Srivastava, Olivia Kopasz-Gemmen, Abhiram Kunamneni, Aaron Thurman, Shota Yoshida, Eden Ozkan, Vinamra Swaroop, Rahul Nanwani, Ajan Arora, Arya Joshi, Om Khuperkar, Mariam Hamed, Mihir Suresh Bharadwaj, Niloy Islam, Adesh Urval, Junying Wang, Sungki Hong & Ken Inoki

  2. Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan

    Keizo Kanasaki & Daisuke Koya

  3. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Ken Inoki

  4. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Ken Inoki

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  1. Swayam Prakash Srivastava
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Contributions

SPS and KI designed, conceptualized, performed in vivo experiments, immunostaining, biochemical assays, qPCR and wrote the paper. OKG, AK, AT, JW, EO, RN, AA, AJ, MH, MSB, KK, and DK also performed immunostaining experiments and quantifications. VS contributed to statistical analyses. SY developed the image analysis program. OK performed western blotting. NI and AU maintained mouse colonies and provided experimental mice, and SH provided experimental methods.

Corresponding authors

Correspondence to Swayam Prakash Srivastava or Ken Inoki.

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Competing interests

The authors declare no competing interests.

Ethics approval

All experimental methods were performed in accordance with the University guidelines and regulations. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Michigan (#PRO00011945) and Kanazawa Medical University animal protocols (#2014-89, #2013-114, and #2014-101).

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Srivastava, S.P., Kopasz-Gemmen, O., Kunamneni, A. et al. AMPK is dispensable for physiological podocyte and glomerular functions but prevents glomerular fibrosis in experimental diabetes. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03078-y

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  • Received: 22 April 2025

  • Revised: 11 February 2026

  • Accepted: 12 March 2026

  • Published: 28 March 2026

  • DOI: https://doi.org/10.1038/s41420-026-03078-y

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