Kidney Week

Abstract: PO2499

Hydrogen Sulfide Ameliorates High Fat Diet-Induced Hypertension and Kidney Injury in Mice

Session Information

• CKD: Metabolism, Epigenetics, and Signaling
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 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

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

Goutam Ghosh-Choudhury,

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

Kumar Sharma,

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

Balakuntalam S. Kasinath,

Background

The role of hyperinsulinemia caused by high fat diet (HFD) in kidney injury is not known. Employing kidney proximal tubule specific insulin receptor (IR) KO mice, we have shown recently that HFD-induced kidney injury requires hyperinsulinemia-induced IR activation (Lee et al., JCI insight, 2021, 6(3): e143619). Furthermore, HFD reduced kidney hydrogen sulfide (H₂S) generation in an IR-dependent manner. We tested if H₂S administration ameliorates HFD-induced kidney injury in mice and cell models.

Methods

5 month-old C57BL6 male mice were placed on normal fat diet (NFD) or HFD for 2 months followed by randomization to receive for 2 months, H₂S as sodium hydrosulfide (NaHS) 30 µmoles/L in drinking water or. water alone (n=5-6 in each group).

Results

HFD or NaHS did not affect blood glucose level. HFD increased body weight, and induced systolic hypertension (NFD: 118 ± 8 vs. HFD: 144 ± 10 mmHg), albuminuria (25.5 ±16 vs. 139.7 ±48 µg/mg), and kidney accumulation of matrix proteins. NaHS reversed these HFD-induced changes (systolic hypertension: 112 ± 7 mmHg, urinary ACR: 76.1 ± 29 µg/mg) without affecting body weight. In the renal cortex, HFD reduced level of H₂S, which was restored by NaHS administration. HFD stimulated IR phosphorylation and inhibited AMPK activity, which promotes synthesis of proteins including matrix proteins. NaHS did not affect IR phosphorylation but increased AMPK activity. We employed proximal tubule cells to test the effect of H₂S on insulin-induced matrix synthesis. Insulin increased fibronectin synthesis likely through stimulation of its mRNA translation by inhibiting AMPK and activating mTORC1. This effect of insulin was abolished by NaHS.

Conclusion

Taking in vivo and in vitro data together, we conclude: (1) HFD induces kidney IR activation and reduces H₂S generation in association with kidney injury. (2) H₂S acts as a signling molecule to activate AMPK, downstream of IR, and inhibits mTORC1 to ameliorate HFD-induced kidney injury. (3) H₂S could be a therapeutic agent for obesity-related kidney injury.