Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy.

Nicotinamide adenine dinucleotide (NAD+) metabolism plays a critical role in kidneys. We previously reported that decreased secretion of a NAD+ precursor, nicotinamide mononucleotide (NMN), from proximal tubules (PTs) can trigger diabetic albuminuria. In the present study, we investigated the role of NMN-producing enzyme nicotinamide phosphoribosyltransferase (Nampt) in diabetic nephropathy. The expression of Nampt in PTs was downregulated in streptozotocin (STZ)-treated diabetic mice when they exhibited albuminuria. This albuminuria was ameliorated in PT-specific Nampt-overexpressing transgenic (TG) mice. PT-specific Nampt-conditional knockout (Nampt CKO) mice exhibited TBM thickening and collagen deposition, which were associated with the upregulation of the profibrogenic gene TIMP-1. Nampt CKO mice also exhibited the downregulation of sirtuins, particularly in Sirt6. PT-specific Sirt6-knockout mice exhibited enhanced fibrotic phenotype resembling that of Nampt CKO mice with increased Timp1 expression. In conclusion, the Nampt-Sirt6 axis in PTs serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.

• Publication year

  2019

• Venue

  Cell Reports

• Publication date

  2019-04-02

• Fields of study

  Biology, Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1016/j.celrep.2019.03.024PMID 30943401
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Electrophoretic Mobility Shift Assay

  2020cited by this paper
• De novo NAD+ synthesis enhances mitochondrial function and improves health

  2018cited by this paper
• De novo NAD+ biosynthetic impairment in acute kidney injury in humans

  2018cited by this paper
• Sirt6 deficiency results in progression of glomerular injury in the kidney

  2017cited by this paper
• TGF-β: the master regulator of fibrosis

  2016cited by this paper
• SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice.

  2015cited by this paper
• TIMP-1 Induces α-Smooth Muscle Actin in Fibroblasts to Promote Urethral Scar Formation

  2015cited by this paper
• The regulation of radiosensitivity by p53 and its acetylation.

  2015cited by this paper
• Neuronal NAMPT is Released after Cerebral Ischemia and Protects against White Matter Injury

  2014cited by this paper
• Reduced tubular proteinuria in hypertensive rats treated with losartan is associated with higher renal cortical megalin expression

  2014cited by this paper
• P53 and Sirt1: routes of metabolism and genome stability.

  2014cited by this paper
• Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in murine models of inflammatory lung injury.

  2014cited by this paper
• Myocardial matrix metalloproteinase-2: inside out and upside down.

  2014cited by this paper
• Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

  2013cited by this paper
• Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.

  2011cited by this paper
• BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy.

  2011cited by this paper
• SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310

  2010cited by this paper
• Altered Retinoic Acid Metabolism in Diabetic Mouse Kidney Identified by 18O Isotopic Labeling and 2D Mass Spectrometry

  2010cited by this paper
• Reactive oxygen species promote caspase-12 expression and tubular apoptosis in diabetic nephropathy.

  2010cited by this paper
• Kidney-specific Overexpression of Sirt1 Protects against Acute Kidney Injury by Retaining Peroxisome Function

  2010cited by this paper
• FoxO1 Mediates an Autofeedback Loop Regulating SIRT1 Expression*

  2010cited by this paper
• Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease.

  2010cited by this paper
• Allelic Depletion of grem1 Attenuates Diabetic Kidney Disease

  2009cited by this paper
• Nicotinamide Phosphoribosyltransferase Regulates Cell Survival Through NAD+ Synthesis in Cardiac Myocytes

  2009cited by this paper
• SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.

  2009cited by this paper
• Impaired tubular uptake explains albuminuria in early diabetic nephropathy.

  2009cited by this paper
• Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression.

  2008cited by this paper
• Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease.

  2008cited by this paper
• Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice.

  2006cited by this paper
• A Novel Mechanism of Tissue Inhibitor of Metalloproteinases-1 Activation by Interleukin-1 in Primary Human Astrocytes*

  2006cited by this paper
• MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates.

  2005cited by this paper
• Physiological and Pathological Changes in Glucose Regulate Brain Akt and Glycogen Synthase Kinase-3*

  2005cited by this paper
• Evidence of apoptosis in human diabetic kidney

  2004cited by this paper
• Transforming growth factor-β1 stimulates collagen matrix remodeling through increased adhesive and contractive potential by human renal fibroblasts

  2004cited by this paper
• Oxidative stress mediates apoptotic changes induced by hyperglycemia in human tubular kidney cells.

  2004cited by this paper
• Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase

  2004cited by this paper
• High glucose‐induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases

  2003cited by this paper
• Podocyte‐specific expression of cre recombinase in transgenic mice

  2003cited by this paper
• Reactive oxygen species and matrix remodeling in diabetic kidney.

  2003cited by this paper
• Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

  2000cited by this paper
• Hypoxia stimulates proximal tubular cell matrix production via a TGF-beta1-independent mechanism.

  1997cited by this paper
• Over‐expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma

  1995cited by this paper
• HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney.

  1994cited by this paper
• Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei.

  1983cited by this paper
• Studies of streptozotocin-induced insulitis and diabetes.

  1977cited by this paper
• Insulin resistance in genetically obese, hyperglycemic mice.

  1971cited by this paper

• NAMPT overexpression enhances the regenerative potential of mesenchymal stromal cell-derived extracellular vesicles in experimental AKI.

  2026cites this paper
• Beyond hyperglycemia: histone modification-mediated epigenetic dysregulation in diabetic retinopathy and nephropathy.

  2026cites this paper
• Friend or foe? The role of SIRT6 on macrophage polarized to M2 subtype in acute kidney injury to chronic kidney disease

  2025cites this paper
• NAD+ prevents chronic kidney disease by activating renal tubular metabolism

  2025cites this paper
• Sirtuins in kidney homeostasis and disease: where are we now?

  2025cites this paper
• Sirt6 regulates the Notch signaling pathway and mediates autophagy and regulates podocyte damage in diabetic nephropathy

  2025cites this paper
• SIRT6 in health and diseases: from molecular mechanisms to therapeutic prospects.

  2025cites this paper
• NAMPT Is A Novel Inhibitor of Vascular Calcification in Chronic Kidney Disease.

  2025cites this paper
• Dehydrozingerone ameliorates renal structure compromised in diabetic nephropathy.

  2025cites this paper
• Targeting mitophagy in diabetic retinopathy: novel insights into SQSTM1/BNIP3L pathway regulated by luteolin

  2025cites this paper
• Burdock Fructooligosaccharide Protects Against Diabetic Nephropathy in Mice by Regulating Nrf2 Signaling

  2025cites this paper
• Renal Tissue-Derived Exosomal miRNA-34a in Diabetic Nephropathy Induces Renal Tubular Cell Fibrosis by Promoting the Polarization of M1 Macrophages

  2024cites this paper
• Ability of NAD and Sirt1 to epigenetically suppress albuminuria

  2024influential citation
• Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.

  2024cites this paper
• Research progress on Sirtuins (SIRTs) family modulators.

  2024cites this paper
• Molecular Challenges and Opportunities in Climate Change-Induced Kidney Diseases

  2024cites this paper
• Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): Updated progress and perspectives.

  2024cites this paper
• Sirtuins in kidney health and disease

  2024cites this paper
• Transcription factor occupancy limits DNA methylation and determines ICAM1 expression in breast cancer

  2024cites this paper
• Epigenetic alterations and memory: key players in the development/progression of chronic kidney disease promoted by acute kidney injury and diabetes.

  2024cites this paper
• Novel Approach to Skin Anti-Aging: Boosting Pharmacological Effects of Exogenous Nicotinamide Adenine Dinucleotide (NAD+) by Synergistic Inhibition of CD38 Expression

  2024cites this paper
• Sirt6 ameliorates high glucose-induced podocyte cytoskeleton remodeling via the PI3K/AKT signaling pathway

  2024cites this paper
• Sirt6 overexpression relieves ferroptosis and delays the progression of diabetic nephropathy via Nrf2/GPX4 pathway

  2024cites this paper
• The role of SIRT1 in kidney diseases

  2024cites this paper
• Nmnat1 Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1

  2024influential citation
• Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease

  2024cites this paper
• Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data

  2024cites this paper
• RUNX3 alleviates mitochondrial dysfunction and tubular damage by inhibiting TLR4/NF‐κB signalling pathway in diabetic kidney disease

  2024cites this paper
• The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease

  2023cites this paper
• Role of sirtuins in metabolic disease-related renal injury.

  2023cites this paper
• Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis

  2023cites this paper
• NAD^+ and mtRNA sensing drive human kidney diseases

  2023cites this paper
• Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

  2023cites this paper
• The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

  2023cites this paper
• Induced pluripotent stem cells-podocytes promote repair in acute kidney injury is dependent on Mafb/CCR5/Nampt axis-mediated M2 macrophage polarization.

  2023cites this paper
• PCK1 Protects against Mitoribosomal Defects in Diabetic Nephropathy in Mouse Models

  2023cites this paper
• Identification of pyroptosis-related genes and potential drugs in diabetic nephropathy

  2023cites this paper
• NAD^+ salvage governs the immunosuppressive capacity of mesenchymal stem cells

  2023cites this paper
• Therapeutic application of traditional Chinese medicine in kidney disease: Sirtuins as potential targets.

  2023cites this paper
• SIRT6’s function in controlling the metabolism of lipids and glucose in diabetic nephropathy

  2023cites this paper
• Bibliometric Analysis of Renal Fibrosis in Diabetic Kidney Disease From 1985 to 2020

  2022cites this paper
• Roles of NAD+ in Acute and Chronic Kidney Diseases

  2022cites this paper
• NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

  2022influential citation
• Urine metabolomics reveals biomarkers and the underlying pathogenesis of diabetic kidney disease

  2022cites this paper
• SIRT6 overexpression retards renal interstitial fibrosis through targeting HIPK2 in chronic kidney disease

  2022cites this paper
• Nicotinamide mononucleotide ameliorates adriamycin-induced renal damage by epigenetically suppressing the NMN/NAD consumers mediated by Twist2

  2022cites this paper
• Adipose-Renal Axis in Diabetic Nephropathy.

  2022cites this paper
• Sirtuin Family and Diabetic Kidney Disease

  2022cites this paper
• SIRT1–SIRT7 in Diabetic Kidney Disease: Biological Functions and Molecular Mechanisms

  2022cites this paper
• The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62

  2022cites this paper
• The significance of NAD + metabolites and nicotinamide N-methyltransferase in chronic kidney disease

  2022cites this paper
• Deficiency of the kidney tubular angiotensin II type1 receptor-associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization.

  2022cites this paper
• Sirtuin 6 affects glucose reabsorption and gluconeogenesis in type 1 diabetes via FoxO1.

  2022cites this paper
• Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy

  2022cites this paper
• Nicotinamide mononucleotide increases cell viability and restores tight junctions in high-glucose-treated human corneal epithelial cells via the SIRT1/Nrf2/HO-1 pathway.

  2022cites this paper
• Enhancing NAD+ Metabolome in Cardiovascular Diseases: Promises and Considerations

  2021cites this paper
• Nampt promotes fibroblast extracellular matrix degradation in stress urinary incontinence by inhibiting autophagy

  2021cites this paper
• Roles of SIRT6 in kidney disease: a novel therapeutic target

  2021influential citation
• The adverse effect of long term intake of Monosodium Glutamate on kidney performance

  2021cites this paper
• Sirtuins as NAD+-dependent deacetylases and their potential in medical therapy

  2021cites this paper
• NAD+ Homeostasis in Diabetic Kidney Disease

  2021cites this paper
• CircRNA circ-ITCH improves renal inflammation and fibrosis in streptozotocin-induced diabetic mice by regulating the miR-33a-5p/SIRT6 axis

  2021cites this paper
• PSC-MSC-Derived Exosomes Protect against Kidney Fibrosis In Vivo and In Vitro through the SIRT6/β-Catenin Signaling Pathway

  2021cites this paper
• Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

  2021influential citation
• Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy

  2021cites this paper
• An updated pharmacological insight of resveratrol in the treatment of diabetic nephropathy.

  2021cites this paper
• Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease

  2021cites this paper
• The Role of Sirtuins in Kidney Diseases

  2020cites this paper
• Emerging roles of SIRT6 in human diseases and its modulators

  2020cites this paper
• Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: From current human evidence to future possibilities

  2020cites this paper
• Sirtuin 6: a potential therapeutic target for cardiovascular diseases.

  2020cites this paper
• Protective effects of luteolin on nephrotoxicity induced by long-term hyperglycaemia in rats

  2020cites this paper
• Upregulation of AMPK Ameliorates Alzheimer’s Disease-Like Tau Pathology and Memory Impairment

  2020cites this paper
• Sestrin2 as a potential therapeutic target for cardiovascular diseases

  2020cites this paper
• Sirt6 Alleviated Liver Fibrosis by Deacetylating Conserved Lysine 54 on Smad2 in Hepatic Stellate Cells

  2020cites this paper
• Inhibition of mTORC1 improves STZ-induced AD-like impairments in mice.

  2020cites this paper
• Trimetazidine Inhibits Renal Tubular Epithelial Cells to Mesenchymal Transition in Diabetic Rats via Upregulation of Sirt1

  2020cites this paper
• AMPK Ameliorates Tau Acetylation and Memory Impairment Through Sirt1

  2020cites this paper
• [Potential significance of NAD+ biology translational research in super-aged Japan].

  2020cites this paper
• Cordyceps militaris polysaccharides exerted protective effects on diabetic nephropathy in mice via regulation of autophagy.

  2019cites this paper