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Predominant Role of Microvascular over Tubular Injury as Driver of Progressive Renal Damage and Fibrosis Post Ischemia Reperfusion Injury

S. Lan1, B. Yang1, M. Dieudé1, J. Sabo-Vatasescu2, A. Karakeussian-Rimbaud2, J. Turgeon2, S. Qi3, N. Patey4, M. Hébert1

1Medicine Faculty, CRCHUM, University of Montreal, Montreal, QC, Canada, 2CRCHUM, Montreal, QC, Canada, 3Department of Surgery, CRCHUM, University of Montreal, Montreal, QC, Canada, 4Department of Pathology and Cell Biology, CHU Saint-Justine, University of Montreal, Montreal, QC, Canada

Meeting: 2019 American Transplant Congress

Abstract number: A94

Keywords: Apoptosis, Endothelial cells, Fibrosis, Renal ischemia

Session Information

Date: Saturday, June 1, 2019

Session Name: Poster Session A: Ischemia Reperfusion & Organ Rehabilition

Session Time: 5:30pm-7:30pm

 Presentation Time: 5:30pm-7:30pm

Location: Hall C & D

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*Purpose: Ischemia-reperfusion injury (IRI) is a major risk factor for allograft dysfunction and chronic renal failure. Although tubular epithelial cells (TEC) are considered the main cellular target, evidence identifies microvascular injury as an important contributor. Caspase-3 activation, a read-out of apoptotic cell death, has been reported in TEC and endothelial cells in acute kidney injury (AKI). The functional and importance of caspase-3 activation in tubular and microvascular demise post-IRI remains ill defined. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis.

*Methods: We performed unilateral renal artery clamping for 30 minutes and contralateral nephrectomy in wild-type mice (C57BL/6) or caspase-3 KO mice. HUVEC (human umbilical vascular endothelial cell) and PT2 TECs (human proximal renal tubular cells) cultures are exposed to hypoxia-reoxygenation treatment to mimic IRI in vivo.

*Results: In vitro, we found that caspase-3 silencing significantly decreased apoptosis in endothelial cells (HUVEC) but increased necrosis in tubular epithelial cells sumitted to hypoxia-reoxygenation treatment. In murine model of IRI, we found that compared with their wild-type counterparts, caspase-3 KO mice in the early stage of AKI had high urinary cystatin C levels, tubular injury scores, and serum creatinine levels. Electron microscopy revealed evidence of tubular epithelial cell necrosis in caspase-3 KO mice, and immunohistochemistry showed upregulation of the necroptosis marker receptor interacting protein kinase 3 (RIPK3) in renal cortical sections. Western blot analysis further demonstrated enhanced levels of phosphorylated RIPK3 in the kidneys of caspase-3 KO mice. In contrast, caspase-3 KO mice had less microvascular congestion and activation in the early and extension phases of AKI. In the long term (3 weeks after IRI), caspase-3 KO mice had reduced microvascular rarefaction and renal fibrosis, as well as decreased expression of a-smooth muscle actin and reduced collagen deposition within peritubular capillaries. Moreover, caspase-3 KO mice exhibited signs of reduced tubular ischemia, including lower tubular expression of hypoxia-inducible factor-1a and improved tubular injury scores.

*Conclusions: Conclusions: These results establish the pivotal importance of caspase-3 in regulating microvascular endothelial cell apoptosis and renal fibrosis after IRI. These findings also demonstrate the predominant role of microvascular over tubular injury as a driver of progressive renal damage and fibrosis after IRI.

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To cite this abstract in AMA style:

Lan S, Yang B, Dieudé M, Sabo-Vatasescu J, Karakeussian-Rimbaud A, Turgeon J, Qi S, Patey N, Hébert M. Predominant Role of Microvascular over Tubular Injury as Driver of Progressive Renal Damage and Fibrosis Post Ischemia Reperfusion Injury [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/predominant-role-of-microvascular-over-tubular-injury-as-driver-of-progressive-renal-damage-and-fibrosis-post-ischemia-reperfusion-injury/. Accessed February 26, 2021.

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