Abstract: TH-PO0226
Tissue-Dependent Opposing Effects of MicroRNA-204 on Hypertension and Kidney Injury
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
- Liu, Jing, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- He, Lishu, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Mishra, Manoj K., Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Wu, Jing (Jason) O., Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Pandey, Rajan, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Therani, Bhavika, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Usa, Kristie, Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
- Geurts, Aron M., Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
- Liu, Pengyuan, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Liu, Yong, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
- Liang, Mingyu, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, United States
Background
Global knockout of miR-204 has contradictory effects on hypertension and renal injury: it substantially attenuates hypertension but leads to profound albuminuria and renal fibrosis in mice treated with UNx/AngII/salt. This finding suggests a highly tissue-specific nature of the role of miR-204.
Methods
To define cell-specific roles, we generated endothelial- and podocyte-specific miR-204 knockout mice. Endothelial cells (ECs) and glomeruli were isolated from mice to perform RNA-seq analysis. Human iPSCs (hiPSCs) with MIR204 deletion were differentiated into ECs and podocytes to assess the molecular pathways by which miR-204 influences hypertension and renal injury.
Results
In the UNx/AngII/salt model, EC-Mir204-/- mice showed 20-30 mmHg reduction in systolic blood pressure (SBP) (n=10, P< 0.05) with reduced vascular remodeling and preserved EC-dependent vasodilation, while albuminuria was unchanged. In contrast, podocyte-specific mir204 loss led to increased albuminuria (1.49 ± 0.41, 6.01 ± 0.34, and 3.80 ± 0.64 mg/24h in Podo-Mir204+/+, Mir204+/-, and Mir204-/-; n=6, 4, 8; p< 0.05) and fibrosis without significant differences in BP. RNA-seq analysis showed that miR-204 target genes Bcl2, an anti-apoptotic gene, and Sox4, a pro-apoptotic gene, were upregulated in ECs and glomeruli, respectively in mice with Mir204 deletion. We generated MIR204-/- hiPSCs to further investigate the tissue-specific and opposing effects of miR-204 on apoptosis. ECs derived from MIR204-/- hiPSCs (iEC-MIR204-/-) exhibited higher Bcl2 compared to wild-type (iEC-WT) (7.19 ± 0.26 vs 6.04 ± 0.16, n=9,3, P<0.05). AngII-induced apoptosis in iEC-WT (% TUNEL positive cells in vehicle vs. AngII: 27.03 ± 1.11 vs. 52.94 ± 6.81, n=8, 8, P< 0.05) was significantly mitigated in iEC-MIR204-/- (29.26 ± 3.64, n=8, P< 0.05). Meanwhile, podocytes derived from MIR204-/- hiPSCs (iPodo-MIR204-/-) displayed higher Sox4 compared to wild-type (iPodo-WT) (1.15 ± 0.07 vs. 0.88 ± 0.05, n=15, 14, P<0.05). AngII-induced elevation of TUNEL- positive cells in iPodo-MIR204-/- (Vehicle vs. AngII: 39.64 ± 2.73 vs. 44.64 ± 2.27 in iPodo-WT, n=4 and 5, NS; 37.68 ± 1.80 vs. 49.87 ± 1.91 in iPodo-MIR204-/-, n=5, 5, P< 0.05) was substantially attenuated by Sox4 knockdown (31.9 ± 1.81, n=5, P<0.05).
Conclusion
The dissociated effects of miR-204 on hypertension and renal injury are likely driven by tissue-specific, opposing regulation of apoptosis in ECs and podocytes.
Funding
- NIDDK Support