Nicotinamide Supplementation Attenuates Renal Interstitial Fibrosis via Boosting the Activity of Sirtuins
Open Access
- 11 January 2021
- journal article
- research article
- Published by S. Karger AG in Kidney Diseases
- Vol. 7 (3), 186-199
- https://doi.org/10.1159/000510943
Abstract
Background: Progressive tubulointerstitial fibrosis (TIF) is the final common pathway leading to ESRD. There is an urgent need to develop effective approaches slowing the progression of TIF. Previous studies showed that systemic supplementation of nicotinamide (NAM) increases renal NAD+ and reverses ischemic-reperfusion induced acute renal injury. However, the role and mechanism of NAM in TIF has been unclear. Methods: In vivo, we injected NAM (0.25 mg/g) 3 days before unilateral ureter obstruction (UUO) till day 7 post-operation. In vitro, mouse primary proximal tubular epithelial cells (PTCs), rat renal NRK-49F cells, and human renal proximal tubular epithelial cell (HK-2) were pretreated with the indicated concentration of NAM 1 h before incubation with transform growth factor-β1 (TGF-β1) or aristolochic acid (AA) for 24 or 48 h. To evaluate the role of sirtuins (SIRTs), PTCs were pretreated with EX527 or resveratrol 30 min before incubation with NAM and TGF-β1. Results: In the present study, we demonstrated that NAM supplementation prevented UUO-induced TIF, and AA-induced renal injury. NAM also decreased the expression of pro-fibrotic proteins and pro-inflammatory cytokines (IL-6 and TNF-α) and attenuated interstitial inflammation. In vitro experiment showed that, NAM inhibited AA-induced G2/M arrest of HK-2 cells by downregulating the expression of cyclin G1, a target gene of p53. In addition, NAM inhibited TGF-β1-induced fibroblast proliferation and activation shown as downregulated expression of collagen I, fibronectin, PCNA, cyclin D1, IL-6, and TNF-α. NAM decreased the acetylation of Smad3 and p53. EX527, an inhibitor of SIRT1, reversed the effect of NAM on TGF-β1-induced matrix protein production. However, resveratrol, a SIRT1 activator, did not further boost the protective effect of NAM on reducing matrix protein production. Conclusions: Taken together, these data indicate that NAM supplementation could inhibit TIF at least partially by boosting the activity of sirtuins.Keywords
This publication has 33 references indexed in Scilit:
- Role of sirtuin-1 in diabetic nephropathyJournal of Molecular Medicine, 2019
- Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and OutcomesAntioxidants and Redox Signaling, 2019
- A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1Journal of Hematology & Oncology, 2017
- Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cellsCellular and Molecular Life Sciences, 2017
- Astaxanthin attenuated pressure overload-induced cardiac dysfunction and myocardial fibrosis: Partially by activating SIRT1Biochimica et Biophysica Acta (BBA) - General Subjects, 2017
- Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance EnzymeTrends in Endocrinology & Metabolism, 2017
- Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal MuscleCell Metabolism, 2016
- PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protectionNature, 2016
- Understanding the mechanisms of kidney fibrosisNature Reviews Nephrology, 2015
- Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in gliomaMolecular Cancer, 2014