Acute kidney injury induces hallmarks of polycystic kidney disease

作者：Kurbegovic Almira; Trudel Marie^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2016, 311(4): F740-F751.

DOI：10.1152/ajprenal.00167.2016

• acute kidney injury
• ischemia/IRI
• polycystin-1 and-2
• mTOR signaling
• Wnt cascade

Acute kidney injury (AKI) and autosomal dominant polycystic kidney disease (ADPKD) are considered separate entities that both frequently cause renal failure. Since ADPKD appears to depend on a polycystin-1 (Pc1) or Pc2 dosage mechanism, we investigated whether slow progression of cystogenesis in two Pkd1 transgenic mouse models can be accelerated with moderate ischemia-reperfusion injury (IRI). Transient unilateral left ischemic kidneys in both nontransgenic and transgenic mice reproducibly develop tubular dilatations, cysts, and typical PKD cellular defects within 3 mo post-IRI. Similar onset and severity of IRI induced-cystogenesis independently of genotype revealed that IRI is sufficient to promote renal cyst formation; however, this response was not further amplified by the transgene in Pkd1 mouse models. The IRI nontransgenic and transgenic kidneys showed from 16 days post-IRI strikingly increased and sustained Pkd1/Pc1 (>3-fold) and Pc2 (>8-fold) expression that can individually be cystogenic in mice. In parallel, long-term and important stimulation of hypoxia-inducible factor 1 alpha expression was induced as in polycystic kidney disease. While mammalian target of rapamycin signaling is activated, stimulation of the Wnt pathway, with markedly increased active beta-catenin and c-Myc expression in IRI renal epithelium, uncovered a similar regulatory cystogenic response shared by IRI and ADPKD. Our study demonstrates that long-term AKI induces cystogenesis and cross talk with ADPKD Pc1/Pc2 pathogenic signaling.

• 出版日期2016-10-1