Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

Gomez, Ivan G.; MacKenna, Deidre A.; Johnson, Bryce G.; Kaimal, Vivek; Roach, Allie M.; Ren, Shen; Nakagawa, Naoki; Xin, Cuiyan; Newitt, Rick; Pandya, Shweta; Xia, Tai He; Liu, Xueqing; Borza, Dorin-Bogdan; Grafals, Mónica; Shankland, Stuart J.; Himmelfarb, Jonathan; Portilla, Didier; Liu, Shiguang; Chau, B. Nelson; Duffield, Jeremy S.

doi:10.1172/jci75852

Cited by 348 publications

(346 citation statements)

References 53 publications

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“…29,[48][49][50][51] Data from the Duffield group suggest that microRNA 21 is an important upstream regulator of the pathway. 52 In conclusion, this study showed that selective deletion of Lkb1 in the kidney induced severe injury over time, characterized by dilated tubules and interstitial fibrosis. Our data indicate that loss of AMPK activity and lower fatty acid oxidation and energy depletion play an important role in the phenotype development, indicating that restoring LKB1 activity in CKD could offer therapeutic benefit.…”

Section: Discussionmentioning

confidence: 64%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

102

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Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1 flox/flox ) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers b-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-a (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism. 27: 439-453, 201627: 439-453, . doi: 10.1681 Renal tubular epithelial cells (TECs) display strict apico-basal polarity. They allow a highly regulated uptake or excretion of substances at its apical surface, while keeping a closed, impenetrable surface through the formation of tight intercellular junctions in the basolateral membrane. The establishment and maintenance of TEC polarity is incompletely understood. The liver kinase B1 (LKB1) is an important regular of polarity. Early studies indicated that single intestinal epithelial cells polarize in a cell-autonomous fashion in response to LKB1 expression. 1 The LKB1 or STK11 gene encodes an evolutionarily conserved serine/threonine protein kinase. Following LKB1 expression, intestinal epithelial cells reorganized their cytoskeleton to form an apical brush border, demonstrating LKB1's critical role in establishing epithelial polarity. On the other hand, the effect of LKB1 on cell polarity appears to be cell type specific and deletion of LKB1 did not alter polarity of lung epithelial and pancreatic cells. 2 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 64%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

102

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“…miR-21 has emerged as a novel drug target for diseases that produce kidney fibrosis. 11,[35][36][37] Anti-miR-21 drugs have been developed, and planning for clinical trials to evaluate safety and efficacy of these drugs in patients with Alport syndrome is underway. Our studies provide genetic proof of principle for preclinical testing of these anti-miR-21 drugs as a new therapeutic approach for PKD.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Lakhia¹,

Hajarnis²,

Williams³

et al. 2015

JASN

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Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4. Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.

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“…On this basis, approaches inhibiting overexpressed miRNAs by antisense oligonucleotides or restoring the expression of downregulated miRNAs by synthetic miRNA mimics have been attempted. miRNA21 in particular is an attractive target because it regulates key metabolic, proinflammatory, and profibrogenic pathways and its hepatic and renal overexpression in NASH and CKD leads to PPAR-a downregulation, SREBP-2 upregulation, mitochondrial dysfunction, and profibrogenic hepatic stellate cell activation and proximal tubular cell epithelialto-mesenchymal transition (EMT) (59,60). Consistently, in experimental models of NASH and CKD, anti-miRNA21 antisense oligonucleotides induced weight loss, normalized metabolic dysregulation, and improved hepatic and renal inflammation and fibrosis, effects at least partly mediated by PPAR-a upregulation (59,60).…”

Section: Potential Pathogenic Mechanisms Contributing To Nafld To Ckdmentioning

confidence: 99%

“…miRNA21 in particular is an attractive target because it regulates key metabolic, proinflammatory, and profibrogenic pathways and its hepatic and renal overexpression in NASH and CKD leads to PPAR-a downregulation, SREBP-2 upregulation, mitochondrial dysfunction, and profibrogenic hepatic stellate cell activation and proximal tubular cell epithelialto-mesenchymal transition (EMT) (59,60). Consistently, in experimental models of NASH and CKD, anti-miRNA21 antisense oligonucleotides induced weight loss, normalized metabolic dysregulation, and improved hepatic and renal inflammation and fibrosis, effects at least partly mediated by PPAR-a upregulation (59,60). Despite these premises, several issues remain, including the stability and selective delivery of the pharmacological modulators to the target organs and long-term safety of this approach because miRNAs also regulate cell proliferation and cell cycle progression in diverse tissues and longterm consequences of its modulation on tumor onset and progression are unclear (15,59).…”

Section: Potential Pathogenic Mechanisms Contributing To Nafld To Ckdmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

Cited by 348 publications

References 53 publications

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

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