Kidney Week

Abstract: TH-PO1153

Mitochondrial Mg2+ Uptake Promotes the AKI-to-CKD Transition and Drives Renal Fibrosis

Session Information

• CKD: Mechanisms, AKI, and Beyond - 1
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Reeves, William Brian, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

William Brian Reeves, MD, FASN

• Wang, Weiwei, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Weiwei Wang, MS

• Madesh, Muniswamy, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Muniswamy Madesh, PhD

• Venkatachalam, Manjeri A., The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Manjeri A. Venkatachalam, MBBS

• Li, Kang, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Kang Li, PhD

Background

We have previously demonstrated that mitochondrial Mg²⁺ uptake, mediated by the Mrs2 Mg²⁺ channel, plays a critical role in the pathogenesis of both ischemic and toxic acute kidney injury (AKI). A significant long-term consequence of AKI is the progression to chronic kidney disease (CKD). Notably, Mrs2-dependent Mg²⁺ influx is potentiated by elevated lactate levels; a hallmark of enhanced glycolytic activity observed during the AKI-to-CKD transition and in various forms of established CKD. Here, we investigated the contribution of Mrs2-mediated mitochondrial Mg²⁺ uptake in the development of renal fibrosis, a key feature of CKD progression.

Methods

The AKI-CKD transition was modeled in mice by prolonged (35 min) unilateral ischemia reperfusion. The non-ischemic kidney was removed on Day 27 and the mice were sacrificed on Day 28. Unilateral ureteral obstruction (UUO) was also used to induce kidney fibrosis. Mrs2 activity was inhibited with CPACC, a specific Mrs2 inhibitor, or genetically via global Mrs2 KO. To isolate the role of Mrs2 in the chronic phase, CPACC (10 mg/kg) was administered beginning three days post-ischemia and continued through day 21, thereby minimizing interference with the acute ischemic response.

Results

After unilateral IRI, mice treated with vehicle (saline) developed atrophy of the ischemic kidney and interstitial fibrosis (as judged by Picrosirius staining), and accumulation of fibrosis markers, including Collagen 1 and α-smooth muscle actin. Functional impairment was evidenced by elevated blood urea nitrogen levels following contralateral nephrectomy. Additionally, markers of maladaptive tubular repair such as increased keratin 20 and decreased villin expression were prominently observed. All of these changes were significantly atttenuated in CPACC-treated mice. Likewise, in the 5 day UUO model, Mrs2 KO mice and CPACC-treated swild type mice exhibited markedly reduced fibrosis than saline-treated wild type mice.

Conclusion

These findings identify the mitochondrial Mg²⁺ channel Mrs2 as a previously unrecognized mediator of the AKI-to-CKD transition and a key driver of renal fibrosis. While further investigation is warranted to delineate the underlying mechanisms and assess the broader relevance across CKD etiologies, Mrs2 represents a promising therapeutic target for halting the progression of kidney disease.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025z6f8w4xr