In Vivo RNA interference models of inducible and reversible sirt1 knockdown in kidney cells

Chuang, P. Y., Xu, J., Dai, Y., Jia, F., Mallipattu, S. K., Yacoub, R., Gu, L., Premsrirut, P. K., He, J. C. (July 2014) In Vivo RNA interference models of inducible and reversible sirt1 knockdown in kidney cells. The American Journal of Pathology, 184 (7). pp. 1940-56. ISSN 0002-9440

URL: http://www.ncbi.nlm.nih.gov/pubmed/24952428
DOI: 10.1016/j.ajpath.2014.03.016

Abstract

The silent mating type information regulation 2 homolog 1 gene (Sirt1) encodes an NAD-dependent deacetylase that modifies the activity of well-known transcriptional regulators affected in kidney diseases. Sirt1 is expressed in the kidney podocyte, but its function in the podocyte is not clear. Genetically engineered mice with inducible and reversible Sirt1 knockdown in widespread, podocyte-specific, or tubular-specific patterns were generated. We found that mice with 80% knockdown of renal Sirt1 expression have normal glomerular function under the basal condition. When challenged with doxorubicin (Adriamycin), these mice develop marked albuminuria, glomerulosclerosis, mitochondrial injury, and impaired autophagy of damaged mitochondria. Reversal of Sirt1 knockdown during the early phase of Adriamycin-induced nephropathy prevented the progression of glomerular injury and reduced the accumulation of dysmorphic mitochondria in podocytes but did not reverse the progression of albuminuria and glomerulosclerosis. Sirt1 knockdown mice with diabetes mellitus, which is known to cause mitochondrial dysfunction in the kidney, developed more albuminuria and mitochondrial dysfunction compared with diabetic mice without Sirt1 knockdown. In conclusion, these results demonstrate that our RNA interference-mediated Sirt1 knockdown models are valid and versatile tools for characterizing the function of Sirt1 in the kidney; Sirt1 plays a role in homeostatic maintenance of podocytes under the condition of mitochondrial stress/injury.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
CSHL Authors:
Communities: CSHL labs
Depositing User: Matt Covey
Date: July 2014
Date Deposited: 02 Apr 2015 14:50
Last Modified: 02 Apr 2015 14:50
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31309

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