Deficiency of the Planar Cell Polarity Protein Intu Delays Kidney Repair and Suppresses Renal Fibrosis after Acute Kidney Injury

Acute kidney injury (AKI) is a clinical syndrome characterized by the abrupt decline of renal function, resulting from sepsis, renal ischemia/reperfusion, or exposure to nephrotoxins.

^, In spite of current technology and hospital care, AKI is accompanied by high rates of mortality and morbidity. Patients who survive the acute phase of AKI bear a long-term recovery stage, and some may progress to chronic kidney disease. Tubular damage is a key pathologic feature of AKI. While complete repair of damaged tubules restores full functionality, partial or maladaptive tubule repair leads to the development of chronic kidney problems, such as chronic inflammation and renal fibrosis. Therefore, kidney repair after AKI is centered on the repair and reconstruction of renal tubules. ^, Planar cell polarity (PCP) refers to the coordinated alignment of cell polarity across the plane of the tissue. Especially, PCP is a determinant of the orientation of cell division, and as a result, plays an essential role in embryonic and organ development. Following kidney injury, renal tubular repair involves dedifferentiation, migration, proliferation, and redifferentiation of surviving tubular cells to reconstruct the tubule. In this process, cell division needs to be oriented longitudinally; otherwise, tubular cell proliferation may lead to the expansion of the lumen, resulting in cyst formation.

Therefore, PCP is hypothesized to be a potentially important cellular event in tubular repair.

PCP is governed by a complex molecular machinery consisting of two-module network (core and Fat protein systems) and effector proteins.

Intu is a key PCP effector protein that accumulates at the base of cilia and basal body in Drosophila . ^, Disruption of Intu in Xenopus and mouse leads to defects in cilia and neural tube closure. ^, Recent work further discovered several INTU mutations in patients with ciliopathy, a set of diseases associated with dysfunctional cilia. Intu protects kidney from ischemic AKI by interacting with, and inducing the degradation of, Stat1.

However, the role of Intu and associated PCP in kidney repair is unknown.

This study was designed to delineate the involvement of PCP in kidney repair after injury. Especially, conditional knockout (KO) mouse models were established where the PCP effector Intu was ablated specifically from renal tubules. KO of Intu delayed kidney recovery and ameliorated renal fibrosis after ischemia/reperfusion injury (IRI). These mice developed less renal fibrosis during unilateral ureteral obstruction (UUO). Mechanistically, Intu KO suppressed senescence but increased cell proliferation and apoptosis in kidney tissues after renal IRI. In cultured renal tubular cells, knockdown of Intu inhibited wound healing in a scratch model. These results support a role for PCP in tubular repair after injury in kidney diseases.