Kidney Week

Abstract: SA-PO0250

A SYNE2-MDM2 Axis Mediates Adaptive Repair to Phenotypically Mitigate the AKI-to-CKD Transition

Session Information

• AKI: Mechanisms - Cell Signaling
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Robichaud, Jielu Hao, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jielu Hao Robichaud, MD

• Ellabbad, Mohamed M., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Mohamed M. Ellabbad, MD

• Afrin, Humayra, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Humayra Afrin, MD, PhD

• Gupta, Navin R., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Navin R. Gupta, MD, FASN

Background

Chronic kidney disease (CKD) is a global health problem. Following AKI, tubules undergo adaptive repair to preserve kidney structure, or maladaptive repair to develop tubular atrophy and interstitial fibrosis. Mechanisms governing the transition from tubular adaptive to maladaptive repair are poorly understood and contributes to a lack of FDA-approved therapy. Human pluripotent stem cell (hPSC)-derived kidney organoids phenotypically model the AKI to CKD transition in our cisplatin model. Unbiased snRNAseq transcriptionally profiled tubules during healthy, adaptive, and maladaptive phases to discern murine double minute 2 (MDM2), a driver of homology-directed repair (HDR) and inhibitor of p53-related cell cycle arrest and apoptosis, as the leading DEG during adaptive repair. Separately, we found that DNA damage triggers cytoplasmic microtubule-to-nuclear transport via the SYNE protein family, to form the Linker of Nucleoskeleton and Cytoskeleton complex, that disrupts DNA repair to trigger senescence. Here we probe the association of tubular DNA damage repair elements, MDM2 and the SYNE family, during the transition from adaptive to maladaptive repair.

Methods

hPSC-derived kidney organoids were subject to transient low-dose cisplatin for 2X/week for 5 treatments, as previously with prior snRNAseq dataset interrogated to reveal a transient association between MDM2 and SYNE2 in adaptive repair tubules undergoing HDR, followed by an inverse relationship during maladaptive repair. High-resolution confocal microscopy determined the expression and localization of MDM2, γH2AX, and Ki67 in nephron epithelia of kidney organoids. Quantitative whole-mount immunostaining of nephrons (PODXL⁺ podocytes, LTL⁺ proximal and CDH1⁺ distal tubules) and interstitial fibrosis (COL1A1⁺) was performed

Results

MDM2 was transiently upregulated in DNA damaged proximal tubules (LTL⁺γH2AX⁺) during adaptive repair (AKI), and reduced in the fibrotic phase (CKD). Small molecule inhibition of MDM2 resulted in impaired tubular Ki67⁺ proliferation associated with premature LTL⁺ tubular atrophy and COL1A1⁺ interstitial fibrosis. siRNA knock-down of SYNE2 restored MDM2 in LTL⁺γH2AX+ proximal tubules to abrogate CKD phenotypes

Conclusion

SYNE2 is an upstream regulator of the conversion from adaptive repair (MDM2^HIGH) to maladaptive repair (MDM2^LOW), whose knockdown retards the phenotypic transition from AKI to CKD.