Kidney Week

Abstract: TH-PO0385

Autophagy-Dependent, Podocyte-Specific AMPK Activation Preserves Glomerular Survival

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Kumar, Ashwani, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Ashwani Kumar, PhD

• Reghuvaran, Anand, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Anand Reghuvaran, PhD

• Lin, Qisheng, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China

Qisheng Lin, PhD

• Da Sacco, Stefano, Children's Hospital Los Angeles, Los Angeles, California, United States

Stefano Da Sacco, PhD

• Caldato Barsotti, Gabriel, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Gabriel Caldato Barsotti, MD

• Tanvir, E M, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

E M Tanvir, PhD

• Shi, Hongmei, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Hongmei Shi, DrPH

• Perincheri, Sudhir, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Sudhir Perincheri, MBBS, PhD

• Ishibe, Shuta, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Shuta Ishibe, MD

• Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States

Laura Perin, PhD

• He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States

John Cijiang He, MD, PhD, FASN

• Menon, Madhav C., Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Madhav C. Menon, MD, MBBS

Background

Glomerulosclerosis (FSGS) shows glomerulomegaly and podocytopenia. In mice, AMPK activation mitigated FSGS. AMPK activates autophagy, and podocytes are high-autophagy cells. Hence, we tested the role of podocyte autophagy as a key downstream mechanism in FSGS.

Methods

Ampk overactivation mice (Rosa^{lox-stop-lox-Prkagm}; Prkagm is an inactivation-resistant Ampk γ-subunit), were crossed to Becn1-floxed mice, and then crossed to Nphs2^Cre/Rosa^lox-DTR-lox mice (DTR- Diphtheria toxin receptor) for podocyte-specific expression/isolation to generate Podo-BEC^fl/fl & AGB mice, respectively (AGB = AMPK excess + autophagy deficiency; Fig 1A). We performed Podocyte Exact Morphology (PEMP), morphometry, and induced injury with Uninephrectomy or Adriamycin (ADR). In vitro (human podocytes), and glomerulus-on-a-chip (GOAC) studies were performed.

Results

Podocyte-specific gene expression was validated by podocyte isolation with DT (1B). By 12-wks, Podo-BEC^fl/fl showed weight loss, more albuminuria, podocytopenia, and glomerulomegaly vs B6 (1C-F). PEMP also confirmed reduced foot process length in Podo-BEC^fl/fl (1G). AGB mice showed only a mild baseline phenotype.
However, after Uninephrectomy stress, AGB showed significant glomerulomegaly vs B6 (1H), but without podocytopenia (1I).
After ADR injury, similarly greater weight loss, albuminuria, podocytopenia, and glomerulomegaly occurred in both Podo-BEC^fl/fl & AGB, vs B6 (1J-M). In vitro, AMPK agonists (MF/PF) protected human podocytes after ADR, an effect lost by autophagy inhibition with 3-methyladenine (3-MA) (1N). Analogously, in the GOAC, AMPK-agonism protected against puromycin-induced albumin leak, while 3-MA mitigated this protection (1O).

Conclusion

Our findings dissect protective mechanisms downstream of podocyte-AMPK activation, showing a role for non-autophagy pathways in homeostasis, but a reliance on podocyte autophagy during injury models.

Acknowledgment

MCM acknowledges funding from the NIH (grant NIH/NIDDK R01DK132274-01)

Fig-1

Funding

• NIDDK Support