title: In vivo RNA interference models of inducible and reversible Sirt1 knockdown in kidney cells.
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.
authors: Division of Nephrology, the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: peter.chuang@mssm.edu.
authors: Peter Y
authors: PY
authors: Chuang
authors: Division of Nephrology, the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Jin
authors: J
authors: Xu
authors: Division of Nephrology, Shanghai Medical College, Fudan University, Zhongshan Hospital, Shanghai, China.
authors: Yan
authors: Y
authors: Dai
authors: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors: Fu
authors: F
authors: Jia
authors: Division of Nephrology, the Department of Medicine, State University of New York at Stonybrook, New York, New York.
authors: Sandeep K
authors: SK
authors: Mallipattu
authors: Division of Nephrology, the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Rabi
authors: R
authors: Yacoub
authors: Renal Division and the Molecular Cell Laboratory for Kidney Disease, Renji Hospital, Shanghai Jiatong University School of Medicine, Shanghai, China.
authors: Leyi
authors: L
authors: Gu
authors: Mirimus, Inc., Cold Spring Harbor, New York, New York.
authors: Prem K
authors: PK
authors: Premsrirut
authors: Division of Nephrology, the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Renal Section, James J. Peter Veterans Administration Medical Center, Bronx, New York.
authors: John C
authors: JC
authors: He
mesh_terms: D000419:Albuminuria; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D004195:Disease Models, Animal; D004317:Doxorubicin; D055785:Gene Knockdown Techniques; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism; D034622:RNA Interference; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004317:Doxorubicin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1