Loss of SAV1 in Kidney Proximal Tubule Induces Maladaptive Repair after Ischemia and Reperfusion Injury

Author:

Moon Daeun1,Padanilam Babu J.2,Park Kwon Moo3,Kim Jinu14ORCID

Affiliation:

1. Department of Anatomy, Jeju National University College of Medicine, Jeju 63243, Republic of Korea

2. Department of Urology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

3. Department of Anatomy, BK21 Plus, and Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea

4. Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Republic of Korea

Abstract

Kidney ischemia and reperfusion injury (IRI) is a significant contributor to acute kidney injury (AKI), characterized by tubular injury and kidney dysfunction. Salvador family WW domain containing protein 1 (SAV1) is a key component of the Hippo pathway and plays a crucial role in the regulation of organ size and tissue regeneration. However, whether SAV1 plays a role in kidney IRI is not investigated. In this study, we investigated the role of SAV1 in kidney injury and regeneration following IRI. A proximal tubule-specific knockout of SAV1 in kidneys (SAV1ptKO) was generated, and wild-type and SAV1ptKO mice underwent kidney IRI or sham operation. Plasma creatinine and blood urea nitrogen were measured to assess kidney function. Histological studies, including periodic acid-Schiff staining and immunohistochemistry, were conducted to assess tubular injury, SAV1 expression, and cell proliferation. Western blot analysis was employed to assess the Hippo pathway-related and proliferation-related proteins. SAV1 exhibited faint expression in the proximal tubules and was predominantly expressed in the connecting tubule to the collecting duct. At 48 h after IRI, SAV1ptKO mice continued to exhibit severe kidney dysfunction, compared to attenuated kidney dysfunction in wild-type mice. Consistent with the functional data, severe tubular damage induced by kidney IRI in the cortex was significantly decreased in wild-type mice at 48 h after IRI but not in SAV1ptKO mice. Furthermore, 48 h after IRI, the number of Ki67-positive cells in the cortex was significantly higher in wild-type mice than SAV1ptKO mice. After IRI, activation and expression of Hippo pathway-related proteins were enhanced, with no significant differences observed between wild-type and SAV1ptKO mice. Notably, at 48 h after IRI, protein kinase B activation (AKT) was significantly enhanced in SAV1ptKO mice compared to wild-type mice. This study demonstrates that SAV1 deficiency in the kidney proximal tubule worsens the injury and delays kidney regeneration after IRI, potentially through the overactivation of AKT.

Funder

Jeju National University Hospital Research Fund of Jeju National University School of Medicine

Publisher

MDPI AG

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