TY - JOUR
T1 - Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates smad2/3
AU - Ma, Zhengwei
AU - Wei, QingQing
AU - Zhang, Ming
AU - Chen, Jiankang
AU - Dong, Zheng
N1 - Funding Information:
The work was supported partly by the grants from National Natural Science Foundation of China (81430017), the National Institutes of Health, and the U.S. Department of Veterans Affairs. Z. Dong was a recipient of Senior Career Scientist award from U.S. Department of Veterans Affairs.
Publisher Copyright:
© 2018, American Physiological Society. All rights reserved.
PY - 2018/12/12
Y1 - 2018/12/12
N2 - 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.
AB - 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.
KW - Diabetic kidney disease
KW - Dicer
KW - Fibrosis
KW - MicroRNA
KW - Smad2/3
KW - Unilateral urethral obstruction
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U2 - 10.1152/ajprenal.00402.2018
DO - 10.1152/ajprenal.00402.2018
M3 - Article
C2 - 30280598
AN - SCOPUS:85058692270
SN - 0363-6135
VL - 315
SP - F1822-F1832
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 6
ER -