Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury

Abstract

Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury.

WNT4 Expression in Primary and Secondary Kidney Diseases: Dependence on Staging

“…Our data to some extent confirm the results of experimental studies by Zhao and coworkers [8] and Wei and coworkers [19] presenting WNT4 as a novel biomarker of kidney tubular injury in minimal change disease and hypertensive mice, as they presented increased WNT4 expression at a time of renal fibrosis appearance and CKD progression.…”

“…At present, our study seems to be the first in humans since, to date, most of the studies on WNT4 gene and protein expression have been performed in rodents [5, 6, 8, 12] or comprised very small groups of patients [13]. To the best of our knowledge, no other reports have presented data on WNT4 gene expression in kidney biopsies of patients with different types of glomerulopathies categorized depending on the type and stage of CKD and correlated with clinicopathological parameters.…”

“…Zhao et al [8] detected the presence of the WNT4 protein in the urine of patients with minimal change disease (MCD) with tubular injury, another disease of an immunological background, and showed that the concentration of WNT4 in urine correlated with histopathological alterations in these patients. In contrast to the clinicopathological characteristics of patients with MCD (normal eGFR and serum creatinine, lack of fibrosis) [8] the kidney biopsies of MN, LN, and IgAN/FSGS of our patients presented glomerular damage and tubulo-interstitial fibrosis. It should be emphasized that in rodent models of MN podocytes become primarily injured through the deposition of immune complexes [14].…”

“…WNT4 protein contributes to the regulation of cell cycle progression during tissue regeneration after experimental acute kidney injury (AKI) [7] and reconstruction of damaged tubular epithelium after subcapsular engraftment of Wnt4 expressing fibroblasts in mice [6]. WNT4 protein level increases in the urine samples of patients with renal tubular injury before eGFR lowering becomes apparent and is considered a sensitive indicator of such an injury [8]. …”

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

“…Protein expression analyzed by immunohistochemistry as previously described [27]. Then, positive staining was scored based on the IOD (integrated optical density).…”