Abstract: TH-PO0259
Cardiac LIM Protein Attenuates TGF-β Signaling While Driving Proliferation and Maladaptive Repair in Injured Proximal Tubule
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Aomura, Daiki, Oregon Health & Science University, Portland, Oregon, United States
- Burfeind, Kevin G., Oregon Health & Science University, Portland, Oregon, United States
- Funahashi, Yoshio, Nagoya Daigaku Igakubu Fuzoku Byoin, Nagoya, Aichi Prefecture, Japan
- Groat, Tahnee, Oregon Health & Science University, Portland, Oregon, United States
- Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
Background
Acute cardiorenal syndrome (CRS-1) is a cause of AKI-CKD transition. Heart-derived cardiac LIM protein (CSRP3) accelerates CKD transition. However, how CSRP3 worsens CKD transition is unknown. We hypothesized that CSRP3 affects cell cycle and repair of injured PT.
Methods
Recombinant CSRP3 (rCSRP3) was administered to primary human proximal tubule cells (hPTCs) and assessed with RNAseq. hPTCs were treated with aristolochic acid (AA) or TGFβ1 and cultured with/without rCSRP3. In vivo, cardiac-specific CSRP3-deleted mice (iCardiacCSRP3KO) and controls underwent 8 minutes of cardiac arrest and cardiopulmonary resuscitation (CA/CPR), a translational model of CRS-1 and analyzed on day 3 after CA/CPR.
Results
RNAseq revealed that rCSRP3 regulated 14 pathways of which 6 related to cell proliferation. rCSRP3 did not increase cell number, cell proliferation, or maladaptive cells in untreated hPTC, assessed with Ki-67, EdU incorporation, or expression of VCAM-1. In AA-injured hPTC, rCSRP3 increased the number of Ki-67 positive cells (40.7±1.8% vs. 27.0±2.4% in control, p=0.03) and expression of VCAM-1 (fold change 1.28±0.19, p=0.02). In the presence of TGFβ1, CSRP3 increased VCAM-1 expression (fold change 1.16±0.05, p=0.03), but reduced expressions of phospho- and total-SMAD3, key drivers for TGFβ-mediated fibrogenesis, concomitant with reduction in SMAD3 and COL1A1 mRNA. SOX9 mRNA was not altered. After CA/CPR, CSRP3 immunopositivity localized in PT around the corticomedullary junction. Total SMAD3 expression was reduced in iCardiacCSRP3KO mice, as were Ki-67-positive cells (0.71±0.44% vs 0.52±0.80% in control, p=0.04), the latter consistent with in vitro results. VCAM-1 expression was not changed by CSRP3KO status.
Conclusion
In proximal tubule cells, CSRP3 mediates cell proliferation and drives maladaptive repair while attenuating SMAD3 in vitro and increasing SMAD3 in vivo, suggesting a decoupling of TGFβ signaling from proliferative signaling. CSRP3 mediation of proliferation and adaptation requires cell injury. Therefore, cardiac CSRP3 has injury context-specific proliferative and maladaptive effects on the proximal tubule which discordantly involve TGFβ signaling in vivo.
Funding
- Veterans Affairs Support