Dysregulated expression but redundant function of the long non-coding RNA HOTAIR in diabetic kidney disease

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Majumder, Syamantak ^{[1, 2, 3]} ; Hadden, Mitchell J. ^{[1, 2]} ; Thieme, Karina ^{[4, 1, 2]} ; Batchu, Sri N. ^{[1, 2]} ; Niveditha, Divya ^[3] ; Chowdhury, Shibasish ^[3] ; Yerra, Veera Ganesh ^{[1, 2]} ; Advani, Suzanne L. ^{[1, 2]} ; Bowskill, Bridgit B. ^{[1, 2]} ; Liu, Youan ^{[1, 2]} ; Vakili, Hana ^{[1, 2, 5]} ; Alghamdi, Tamadher A. ^{[1, 2]} ; White, Kathryn E. ^[6] ; Geldenhuys, Laurette ^[7] ; Siddiqi, Ferhan S. ^[8] ; Advani, Andrew ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] St Michaels Hosp, Keenan Res Ctr Biomed Sci, 209 Victoria St, Toronto, ON M5C 1T8 - Canada

^[2] St Michaels Hosp, Li Ka Shing Knowledge Inst, 209 Victoria St, Toronto, ON M5C 1T8 - Canada

^[3] Birla Inst Technol & Sci BITS, Dept Biol Sci, Pilani, Rajasthan - India

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[5] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX - USA

^[6] Newcastle Univ, Electron Microscopy Res Serv, Newcastle Upon Tyne, Tyne & Wear - England

^[7] Dalhousie Univ, Dept Pathol, Halifax, NS - Canada

^[8] Dalhousie Univ, Dept Med, Halifax, NS - Canada

• Tipo de documento: Artigo Científico
• Fonte: Diabetologia; v. 62, n. 11, p. 2129-2142, NOV 2019.
• Citações Web of Science: 0

Resumo

Aims/hypothesis Long non-coding RNAs (lncRNAs) are garnering increasing attention for their putative roles in the pathogenesis of chronic diseases, including diabetic kidney disease (DKD). However, much about in vivo lncRNA functionality in the adult organism remains unclear. To better understand lncRNA regulation and function in DKD, we explored the effects of the modular scaffold lncRNA HOTAIR (HOX antisense intergenic RNA), which approximates chromatin modifying complexes to their target sites on the genome. Methods Experiments were performed in human kidney tissue, in mice with streptozotocin-induced diabetes, the db/db mouse model of type 2 diabetes, podocyte-specific Hotair knockout mice and conditionally immortalised mouse podocytes. Results HOTAIR was observed to be expressed by several kidney cell-types, including glomerular podocytes, in both human and mouse kidneys. However, knockout of Hotair from podocytes had almost no effect on kidney structure, function or ultrastructure. Glomerular HOTAIR expression was found to be increased in human DKD, in the kidneys of mice with streptozotocin-induced diabetes and in the kidneys of db/db mice. Likewise, exposure of cultured mouse podocytes to high glucose caused upregulation of Hotair expression, which occurred in a p65-dependent manner. Although HOTAIR expression was upregulated in DKD and in high glucose-exposed podocytes, its knockout did not alter the development of kidney damage in diabetic mice. Rather, in a bioinformatic analysis of human kidney tissue, HOTAIR expression closely paralleled the expression of its genic neighbour, HOXC11, which is important to developmental patterning but which has an uncertain role in the adult kidney. Conclusions/interpretation Many lncRNAs have been found to bind to the same chromatin modifying complexes. Thus, there is likely to exist sufficient redundancy in the system that the biological effects of dysregulated lncRNAs in kidney disease may often be inconsequential. The example of the archetypal scaffold lncRNA, HOTAIR, illustrates how lncRNA dysregulation may be a bystander in DKD without necessarily contributing to the pathogenesis of the condition. In the absence of in vivo validation, caution should be taken before ascribing major functional roles to single lncRNAs in the pathogenesis of chronic diseases. (AU)

• Processo FAPESP: 16/04591-1 - RNAs não codificantes na doença renal diabética
• Beneficiário: Karina Thieme
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado