Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates smad2/3

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3 Scopus citations

Abstract

Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT-Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT-Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointersti-tial fibrosis. Meanwhile, PT-Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT-Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2–3 mo old), significantly more Smad2/3 was induced in obstructed PT-Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.

Original languageEnglish (US)
Pages (from-to)F1822-F1832
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number6
DOIs
StatePublished - Dec 12 2018

Keywords

  • Diabetic kidney disease
  • Dicer
  • Fibrosis
  • MicroRNA
  • Smad2/3
  • Unilateral urethral obstruction

ASJC Scopus subject areas

  • Physiology
  • Urology

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