Kidney Week

Abstract: FR-PO1221

Factor H Deficiency Exacerbates Endothelial Dysfunction in CKD

Session Information

• CKD: Mechanisms, AKI, and Beyond - 2
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Sun, Mingyao, University of Iowa Health Care, Iowa City, Iowa, United States

Mingyao Sun, PhD

• Xie, Jian, University of Iowa Health Care, Iowa City, Iowa, United States

Jian Xie, PhD

• Huang, Chou-Long, University of Iowa Health Care, Iowa City, Iowa, United States

Chou-Long Huang, MD, PhD

• Smith, Richard J., University of Iowa Health Care, Iowa City, Iowa, United States

Richard J. Smith, MD

• Thurman, Joshua M., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Joshua M. Thurman, MD, FASN

• Jalal, Diana I., University of Iowa Health Care, Iowa City, Iowa, United States

Diana I. Jalal, MD, FASN

Background

Complement dysregulation contributes kidney and cardiovascular disease (CVD). Factor H (FH), a key regulator of the alternative complement pathway (AP), may play a protective role, as rare and common FH variants are predictors of kidney and CVD. Previously, our group demonstrated AP activation in individuals with non-immune-mediated chronic kidney disease (CKD). We hypothesized that FH deficiency exacerbates CKD-induced complement dysregulation and endothelial dysfunction in mice.

Methods

Wild-type (WT), FH+/-, and FH-/- mice were subjected to sham or 5/6 nephrectomy (5/6Nx) surgeries. Glomerular filtration rate (GFR) was evaluated by transcutaneous measurement of clearance of FITC-sinistrin. Plasma FD, FH, C3a and C3 were analyzed via ELISA. We measured aortic ring vascular reactivity by wire myography. Endothelium-dependent and -independent dilation were determined by dose-response curves of acetylcholine (Ach,10⁻⁹–10⁻⁵ M) and sodium nitroprusside (SNP, 10⁻⁹–10⁻⁵ M), respectively, on phenylephrine (PE, 10⁻⁶ M)-induced pre-contracted vessels.

Results

All 5/6Nx groups showed significantly reduced GFR compared to sham, with comparable GFR among sham-operated mice (WT: 210.8±54.9; FH+/−: 275.8±86.8; FH−/−: 202.9±67.2 μL/min), and an approximate 50% decline with 5/6Nx (WT: 116.2±36.5; FH+/−: 135.4±65.8; FH−/−: 102.0±38.3 μL/min). FD levels were elevated across all 5/6Nx groups vs sham counterparts, while FH levels were unchanged. C3a levels tended to increase in WT 5/6Nx mice vs sham and increased significantly in FH+/− and FH-/- 5/6Nx mice vs sham counterparts (from 62.3±30.6 to 296.0±128.8 μg/mL, P=0.002 and from 91.8±41.7 to 171.3±75.1 μg/mL, P=0.05, respectively). Endothelium-dependent vasodilation at ACh 10^-5 was significantly impaired in 5/6Nx mice vs sham among all genotypes while SNP-mediated dilation did not differ between the comparison groups. ACh 10^-5 values for FH+/− 5/6Nx and FH−/− 5/6Nx mice vs sham were (33.1±11.7% vs. 17.9±6.3%, P=0.001 and 38.7±7.4%vs. 25.2±7.8%, P=0.01). In addition, progressive C3 consumption and impaired Ach-mediated dilation were abserved from WT to FH+/− to FH−/− mice.

Conclusion

Consistent with prior observations in humans, CKD via 5/6Nx induced AP lability and endothelial dysfunction. FH deficiency further exacerbated AP dyregulation leading to AP activation and worsened endothelial dysfunction in this CKD model.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025s55y8k0a