Kidney Week

Abstract: FR-PO1196

Kidney Proximal Tubule AMP-Activated Protein Kinase (AMPK) Contributes to Hydrogen Sulfide Amelioration of High-Fat Diet-Induced Kidney Injury

Session Information

• CKD: Mechanisms, AKI, and Beyond - 2
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Hak Joo Lee, PhD

• Das, Falguni, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Falguni Das, PhD

• Min, Liang, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Liang Min, MD, PhD

• Gao, Jingli, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Jingli Gao

• Montellano, Richard, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Richard Montellano

• Ghosh-Choudhury, Goutam, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Goutam Ghosh-Choudhury, MS, PhD

• Kasinath, Balakuntalam S., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Balakuntalam S. Kasinath, MD, FASN

• Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Kumar Sharma, MD, FASN

Group or Team Name

• Center for Precision Medicine.

Background

We have reported that high fat diet (HFD)-induced kidney injury is associated with hydrogen sulfide (H₂S) deficiency, insulin receptor (InsR) activation, and inhibition of AMP-activated protein kinase (AMPK) resulting in stimulation of mTORC1-mediated fibronectin accumulation; sodium hydrosulfide (NaHS, a H₂S source) rescued the injury phenotype. Whether AMPK activation is essential for protection afforded by H₂S remains unknown.

Methods

To address this question, C57BL6 WT and kidney proximal tubule specific AMPKa2 KO (KTAMPKa2KO) male mice were placed on normal fat diet (NFD) or HFD for 2 months followed by randomization to NaHS in drinking water for 2 months.

Results

HFD increased body weight, systolic blood pressure, albuminuria, and kidney accumulation of matrix proteins in WT and KTAMPKa2KO mice. NaHS did not affect body weight; it ameliorated HFD-induced injury in WT although the protection was attenuated in KTAMPKa2KO mice. In the renal cortex, HFD reduced H₂S generation and AMPK activity and induced InsR-mTORC axis stimulation which promotes synthesis of proteins including fibronectin. NaHS reversed HFD-induced changes in WT mice by restoring AMPK activity but not in KTAMPKa2KO mice. In vitro in proximal tubular epithelial (MCT) cells, NaHS restored insulin-induced AMPK inactivation and mTORC activation in kidney. Compound C, an AMPK selective inhibitor, abolished NaHS effect on insulin-induced matrix protein accumulation in MCT cells.

Conclusion

Taking in vivo and in vitro data together, we conclude: (1) HFD induces kidney InsR activation and H₂S deficiency in association with kidney injury. (2) AMPK activation is required for the beneficial effect of H₂S to ameliorate HFD-induced changes. (3) H₂S could be a therapeutic target for obesity-related kidney injury.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20259b6vm6qm