Kidney Week

Abstract: SA-PO075

Myeloid Cells Alleviate Kidney Fibrosis after Folic Acid-Induced AKI via Vascular Endothelial Growth Factor (VEGF)-A Signaling

Session Information

• AKI: Inflammation and Cell Cycle
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Ono, Kazutoshi, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan

Kazutoshi Ono, MD, PhD

• Isagawa, Takayuki, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan

Takayuki Isagawa, PhD

• Nagata, Daisuke, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan

Daisuke Nagata, MD, PhD

• Takeda, Norihiko, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan

Norihiko Takeda, MD, PhD

Background

Tubular epithelial cells (TEC) consume oxygen and nutrients to maintain its physiological function. Peritubular capillaries (PTC) maintain oxygen environment in kidney tissues, and its density is correlated with renal function and its prognosis. In healthy kidney, TEC act as a predominant source of vascular endothelial growth factor-A (VEGF-A) a major angiogenic cytokine which is required for the maintenance of PTC. However, how do angiogenesis and subsequent tissue repair take place in acute kidney injury (AKI) or its transition to chronic kidney disease (CKD) are largely unknown.

Methods

The mouse folic acid acute kidney injury (FA-AKI) model was used as an AKI model. We first performed histological and gene expression analysis of the kidneys of the wild-type mice over time after FA-AKI. Next, we performed single-cell RNA-sequencing (scRNA-seq) on kidneys of the wild-type mice 7 days after FA-AKI to detect VEGF-A-producing cells where TEC decreased.

Results

Histological analysis showed that proximal TEC and PTC gradually decreased until day 14 after FA-AKI. The mRNA expression levels of kidney Vegfa and Megalin (proximal TEC specific gene) were significantly lower on day 2 compared to baseline. Megalin was still lower on days 7 and 14, whereas Vegfa increased on days 7 and 14. ScRNA-seq revealed that the major source of Vegfa was macrophages (MΦ) among the leukocytes accumulated in the kidney 7 days after FA-AKI. In addition, fluorescence-activated cell sorting showed that F4/80^lo MΦ and F4/80^hi MΦ subpopulations accumulated biphasically in the kidney after FA-AKI, and F4/80^lo MΦ expressed higher levels of Vegfa than F4/80^hi MΦ. Finally, we generated myeloid cell-specific VEGF-A conditional knockout mice (mVEGFA CKO: LysM-Cre Vegfa^flox/flox) and controls (Control: Vegfa^flox/flox). PTC formation and TEC regeneration were significantly suppressed and tissue fibrosis was more pronounced in mVEGF-CKO compared to Control 14 days after FA-AKI.

Conclusion

Our data suggest that kidney macrophages substitute VEGF-A production in AKI where TEC derived VEGF-A secretion is impaired. Kidney macrophages have a potential as a therapeutic target in the management of AKI. Further study regarding how macrophages accumulate and produce VEGF-A in kidney tissues will help us to understand the pathological process of AKI to CKD transition.