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Cellular communication network factor 2 (CCN2) promotes the progression of acute kidney injury to chronic kidney disease.

Biochemical and biophysical research communications (2019-07-20)
Tsutomu Inoue, Takeru Kusano, Hiroaki Amano, Hidetomo Nakamoto, Hirokazu Okada
ABSTRACT

Here we evaluated the efficacy of depleting cellular communication network factor 2 (CCN2) produced by renal tubular epithelial cells in preventing the progression of severe acute kidney injury (AKI) to chronic kidney disease (CKD). We used conditional Ccn2 knockout mice in which expression of Ccn2 was controlled by γ-glutamyl transpeptidase promoter-regulated Cre recombinase. AKI was induced by ischemia-reperfusion injury. An effect of inhibiting Ccn2 expression by tubular epithelial cells on acute damage, assessed according to the levels of kidney injury molecule-1, was not detected 3 days after injury. However, by day 14, interstitial fibrosis and the levels of the extracellular matrix and profibrotic cytokines were reduced in Ccn2 knockout mice compared with wild-type mice. The ectopic expression of the pan-caspase inhibitor p35 reduced the number of apoptotic cells in damaged tubular epithelial cells 3 days after ischemia-reperfusion injury. In contrast, interstitial fibrosis was exacerbated, accompanied by increased levels of transforming growth factor-β and plasminogen-activator inhibitor-1 14 days after insult. Depletion of CCN2 from tubular epithelial cells slowed the progression of interstitial fibrosis, which was promoted by ectopic expression of p35 in the same cells. These results indicate that tubular epithelial cells, which should be eliminated by apoptosis during physiological repair of AKI, produced CCN2 in the damaged kidney and that CCN2 expression in damaged tubular epithelial cells made a critical contribution to the transition from AKI to CKD. Moreover, inhibiting CCN2 expression may represent a therapeutic approach for preventing the progression of AKI to CKD, irrespective of the stage of kidney disease.

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Anti-Fibronectin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution