ANRIL regulates multiple molecules of pathogenetic significance in diabetic nephropathy

Abstract

Background Hyperglycemia-induced transcriptional alterations lead to aberrant synthesis of a large number of pathogenetic molecules leading to functional and structural damage to multiple end organs including the kidneys. Diabetic nephropathy (DN) remains a major cause of end stage renal disease. Multiple epigenetic mechanisms, including alteration of long non-coding RNAs (lncRNAs) may play a significant role mediating the cellular transcriptional activities. We have previously shown that lncRNA ANRIL may mediate diabetes associated molecular, functional and structural abnormalities in DN. Here we explored downstream mechanisms of ANRIL alteration in DN. Methods We used renal cortical tissues from ANRIL knockout (KO) mice and wild type (WT) mice, with or without streptozotocin (STZ) induced diabetes for RNA sequencing. The differentially expressed genes were identified using edgeR and DESeq2 computational methods. KEGG and Reactome pathway analyses and network analyses using STRING and IPA were subsequently performed. Results Diabetic animals showed hyperglycemia, reduced body weight gain, polyuria and increased urinary albumin. Both albuminuria and polyuria were corrected in the KO diabetic mice. RNA analyses showed Diabetes induced alterations of a large number of transcripts in the wild type (WT) animals. ANRIL knockout (KO) prevented a large number of such alterations. The altered transcripts include metabolic pathways, apoptosis, extracellular matrix protein synthesis and degradation, NFKB related pathways, AGE-RAGE interaction pathways etc. ANRIL KO prevented majority of these pathways. Conclusion These findings suggest that as ANRIL regulates a large number of molecules of pathogenetic significance, it may potentially be a drug target for DN and other chronic diabetic complications.

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

“…To examine molecular mechanisms of mortality induced by established models of agingrelated diseases, we preprocessed 9 publicly available datasets with gene expression profiles of tissues from animals representing models of Alzheimer's disease (AD) (brain and pineal gland) 101 , chronic kidney disease (CKD) (kidney) 102 , diabetic neuropathy (DN) (kidney) 103 , ischemic stroke (IS) (heart, brain and microglia cells) [104][105][106] , nonalcoholic steatohepatitis (NASH) (liver) 107 , and hepatocellular carcinoma (HCC) (liver) 108 , along with age-matched controls. Multi-tissue chronological and mortality clocks revealed a statistically significant acceleration of biological age in all examined disease models and organs, except for HCC (Fig.…”