Table 2.
Role of Sirtuin family in diabetic kidney diseases.
| Sirtuin family | Animal model | Cell model | Sirtuin related Reagent | Molecular biology | Pathophysiology | References |
|---|---|---|---|---|---|---|
| SIRT1 | — | SV40 MES13 | — | Smad7 deacetylation | attenuate mesangial cell apoptosis | (51) |
| SIRT1 | STZ-induced Sprague–Dawley rats | — | SIRT1 activator, resveratrol | change histone H3 phosphorylation, MAP kinase p38, SIR2 and p53 expression | — | (52) |
| SIRT1 | — | HK-2 | — | activate FoxO3a and catalase | release renal tubular cell apoptosis | (53) |
| SIRT1 | db/db mice | mouse PTC | SIRT1 activator, resveratrol | regulate MnSOD activity | ameliorate oxidative stress in proximal tubules | (54) |
| SIRT1 | db/db C57BLKS mice | mouse CIP | — | FoxO4 deacetylation | prevent podocyte apoptosis | (55) |
| SIRT1 | diabetic Wistar fatty and lean rats | — | — | NFκB deacetylation | improve mitochondrial morphology and autophagosomes | (56) |
| SIRT1 | aldosterone-induced mitochondrial dysfunction C57BL/6J mice | MPC5 | SIRT1 activator, resveratrol | regulate PGC1α | reduce aldosterone-induced mitochondrial dysfunction and podocyte injury | (57) |
| SIRT1 | STZ-induced Sprague-Dawley rats | — | SIRT1 activator, resveratrol | activate FoxO1 | regulate oxidative stress and fibrosis | (58) |
| SIRT1 | db/db C57BLKS/J mice | rat MC | SIRT1 activator, resveratrol | activate PGC1α, ERR1α, and SREBP1, decrease PI3K, Akt, FoxO3a | ameliorate glomerular matrix expansion and inflammation | (59) |
| SIRT1 | STZ-induced Sprague-Dawley rats | rat MC | SIRT1 activator, resveratrol | activate Nrf2/ARE, reduce fibronectin and TGFβ1, increase HO1 | reduce mesangial cell oxidative stress | (60) |
| SIRT1 | kidney- and proximal tubules-specific Sirt1 knockout, STZ-, FK866-, 5/6 Nephrectomy-induced nephrectomized and db/db mice | mouse CIP, HK-2 | — | epigenetically suppress Claudin1 | participate in crosstalk between podocytes and renal tubules: SIRT1 in proximal tubules protects against albuminuria by maintaining NMN around glomerulus, thus influencing podocyte function | (61) |
| SIRT1 | STZ-induced Sprague-Dawley rats | mouse CIP, mouse GEC | SIRT1 activator, resveratrol | down-regulate VEGF and VEGFR2 | regulate angiogenesis in podocyte and endothelial cells | (62) |
| SIRT1 | db/db, podocyte-specific Sirt1 knockout mice | human CIP | — | NFκB and STAT3 deacetylation | attenuate proteinuria and podocyte injury | (63) |
| SIRT1 | STZ-induced Sprague–Dawley rats | — | — | increase HO1, loss FoxO1 | suppress oxidative stress and extracellular matrix deposition | (64) |
| SIRT1 | STZ-induced diabetic spontaneously hypertensive rats | human MC | — | decrease NOX4 and TGFβ1, maintaining PARP1, intracellular NAD+/NADH ratio, AMP/ATP ratio, Smad3 deacetylation | ameliorate mesangial cell extracellular matrix accumulation | (65) |
| SIRT1 | STZ-induced, Sirt1 transgenic C57BL/6J mice | HEK293A | — | regulate p300, ET1 and TGFβ1 | protect from renal injury | (66) |
| SIRT1 | — | rat MC | SIRT1 activator, resveratrol | inhibit HIF1α | inhibit mesangial cell inflammation and fibrosis | (67) |
| SIRT1 | db/db C57BLKS/J mice | human GEC | SIRT1 activator, resveratrol | decrease FoxO1, FoxO3a, and SREBP1, increase PPARγ, PGC1α, ERR1α, and pACC | ameliorate lipotoxicity, oxidative stress, apoptosis and endothelial cell dysfunction | (68) |
| SIRT1 | STZ-induced Wistar rats | — | SIRT1 activator, resveratrol | normalize TGFβ1, fibronectin, NFκB, Nrf2, and FoxO1 | protect renal oxidative damage | (69) |
| SIRT1 | STZ-induced Wistar rats | HK-2 | SIRT1 activator, resveratrol | p53 deacetylation | ameliorate renal tubular injury | (70) |
| SIRT1 | STZ-induced Wistar albino rats | — | — | inhibit NFκB | alleviate renal oxidative stress | (71) |
| SIRT1 | STZ-induced eNOS−/− mice | mouse CIP | — | down-regulate NOX4, increase NFκB deacetylation | attenuates podocytes injury | (72) |
| SIRT1 | OVE26 mice, podocyte-specific Sirt1 overexpression mice | human CIP | SIRT1 agonist, BF175 | activate PGC1α | attenuate podocyte loss and glomerular oxidative stress | (73) |
| SIRT1 | db/db C57BL/KsJ mice | mouse MC | — | regulate HIF1α | alleviate mesangial cell proliferation and renal fibrosis | (74) |
| SIRT1 | db/db C57BL/6 mice | LLC-PK1 porcine renal epithelial cells | — | up-regulate GLUT2, down-regulate SGLT2 | high basolateral glucose in renal tubules increases SGLT2 and decreases SIRT1 and GLUT2 | (75) |
| SIRT1 | — | HK-2 | — | regulate LC3II, ATG5 and ATG7 | regulate autophagy and fibrosis in renal proximal tubules | (76) |
| SIRT1 | OLETF rats | HK-2, HEK293T | — | regulate TGFβ1 | attenuate EMT and proximal tubule cell fibrosis | (77) |
| SIRT1 | STZ-induced diabetic CD-1 mice | mouse CIP | SIRT1 activator, resveratrol | regulate PGC1α, increased MnSOD, inhibit ROS | attenuation of mitochondrial oxidative stress, inhibit podocyte and renal tubular epithelial cell apoptosis | (78) |
| SIRT1 | STZ-induced Sprague–Dawley rats | — | — | up-regulate Nrf2/HO1 | renal tubules dysfunction and oxidative stress | (79) |
| SIRT1 | STZ-induced C57BL/6J mice | — | — | regulate PGC1α | improve kidney fibrosis and mitochondrial biogenesis | (80) |
| SIRT1 | — | HEK293 | — | down-regulate phosphorylate mTOR | prevent kidney cell damage | (81) |
| SIRT1 | STZ-induced C57BL/6J mice with HFD | — | — | activate AMPK/PGC1α | improve renal fibrosis, inflammation, and oxidative stress | (82) |
| SIRT1 | STZ-induced C57BL/6 mice | human CIP, rat GEC, rat MC | — | PGC1α and FoxO1 deacetylation | balance mitochondrial dysfunction, biogenesis, and mitophagy, regulate podocyte injury and proteinuria | (83) |
| SIRT1 | STZ-induced Sprague–Dawley rats | rat MC | — | regulate FoxO1 | alleviate abnormal mesangial cells proliferation | (84) |
| SIRT1 | STZ-induced C57BL/6 mice | mouse MC | — | regulate PGC1α, Nrf1, mtTFA, mtDNA copy, and ATP | affect mitochondrial biogenesis and function in mesangial cells | (85) |
| SIRT1 | STZ-induced Sprague–Dawley rats with HFD | — | SIRT1 inhibitor, EX527 | regulate FoxO1 | alleviate oxidative stress and structural changes of glomerulus, inhibit extracellular matrix | (86) |
| SIRT1 | STZ-induced CD1 mice, db/db C57BLKS/J mice | human CIP | SIRT1 activator, resveratrol; SIRT1 inhibitor, EX527 | phosphorylation SIRT1 S47 to S47A decrease ROS and cytochrome c release, increase ATP | regulate podocyte mitochondrial function | (87) |
| SIRT1 | STZ- induced C57BL/6J mice with HFD | mouse CIP | — | inhibit NFκB | inhibit podocyte oxide stress and inflammation | (88) |
| SIRT1 | STZ-induced Sprague–Dawley rats | — | — | inhibit NLRP3, IL1β, TNFα and NFκB | regulate renal oxidant-antioxidant balance, dampen inflammation, attenuate collagen accumulation | (89) |
| SIRT1 | STZ-induced Sprague–Dawley rats with HFD | mouse CIP | — | activate phosphorylate AMPK and inhibit phosphorylate NFκB | block podocyte oxidative stress and inflammatory responses | (90) |
| SIRT1 | STZ induced Wistar rats | — | — | inhibit phosphorylate FoxO3a, Claudin1 | suppress renal oxidative stress | (91) |
| SIRT1 | db/db C57BL/6J mice | MPC5, rat MC, GEC, HK-2, NRK-52E, RAW 264.7 | — | activate AMPK-SREBP1 | participate in podocyte lipid metabolism | (92) |
| SIRT1 | STZ-induced C57BL/6 mice | HK-2 | SIRT1 inhibitor, EX-527 | induce NFκB and STAT3 dephosphorylation and deacetylation | reduce tubular epithelial cell oxidative stress, apoptosis, inflammation response, and EMT | (93) |
| SIRT1 | db/db C57BLKs/J mice | SV40 MES13 | SIRT1 inhibitor, EX527 | compete with PARP1 for NAD+, activate AMPK/PGC1α | ameliorate mesangial cell extracellular matrix accumulation | (94) |
| SIRT1 | STZ-induced C57BL/6 mice with HFD | — | — | upregulate PGC1α | upregulate in diabetic mice kidney | (95) |
| SIRT2 | caloric restriction C57BL/6 mice | HEK293, HEK293T | — | FoxO3a deacetylation, increase FoxO DNA binding, Kip1, MnSOD, and Bim | oxidative stress increases SIRT2 in kidney cells | (96) |
| SIRT1 and SIRT3 | — | rat MC | — | maintaining intracellular NAD+/NADH ratio, blocked Akt, augmented AMPK, prevent mTOR | inhibit mesangial cell hypertrophy | (97) |
| SIRT1 and SIRT3 | Zucker Diabetic Fatty Rats with HFD | — | SIRT1 inhibitor, EX527 | regulate Claudin1 | revealed expansion of the extracellular mesangial matrix and suppression of glomerulosclerosis | (98) |
| SIRT3 | — | HK-2 | — | regulate Akt/FoxO1 and FoxO3a activity | antagonize tubular epithelial cell apoptosis | (99) |
| SIRT3 | Zucker Lean Rats and Zucker Diabetic Fatty Rats | HK-2 | — | IDH2 deacetylation, decrease SOD2, CD38, increase NAD+/NADH ratio | decrease tubular cell damage, mitochondrial oxidative stress and morphologic alterations | (100) |
| SIRT3 | STZ-induced CD-1 and C57Bl6 KsJ mice, Akita mice | HK-2 | — | inhibit TGFβ1/Smad3, HIF1α, and PKM2 dimer formation | abnormal glycolysis and EMT in tubular epithelial cells | (101) |
| SIRT3 | — | HK-2 | — | increase phosphorylated Akt and FoxO3a | protect tubular epithelial cells against oxidative stress and apoptosis | (102) |
| SIRT3 | db/db C57BL/6J mice | mouse PTC | SIRT3 inhibitor, 3-TYP | inhibit BNIP3 | ameliorates oxidative stress and cell apoptosis in proximal tubular cells | (103) |
| SIRT3 | BTBR ob/ob mice | — | — | activate SOD2, restore PGC1α | attenuate albuminuria, ameliorate glomerular damage, reduce podocyte injury, tubule-glomerulus retrograde interplay | (104) |
| SIRT3 | Zucker Lean Rats and Zucker Diabetic Fatty Rats | HK-2 | — | restore intracellular NAD +/NADH ratio | reduce tubulointerstitial fibrosis and tubular cell damage | (105) |
| SIRT3 | STZ-induced Wistar rats with HFD | — | — | activate PGC1α and SOD2 | maintaining mitochondrial redox equilibrium | (106) |
| SIRT4 | — | mouse CIP | — | down-regulate NOX1, Bax and phosphorylated p38, up-regulate Bcl2, attenuate TNFα, IL1β and IL6 | inhibit podocyte apoptosis | (107) |
| SIRT6 | podocyte-specific Sirt6 knockout, STZ-induced diabetic, adriamycin-induced nephropathy, db/db C57BL/6 mice | rat MC, rat GEC, HK-2, human CIP | — | histone H3K9 deacetylation, inhibit Notch1 and Notch4 transcription | exacerbate podocyte injury and proteinuria | (44) |
| SIRT6 | STZ-induced C57BL/6 mice | human CIP | — | increase H3K9ac and H3K56ac | suppress mitochondrial dysfunction and apoptosis in podocytes | (108) |
| SIRT6 | STZ-induced C57BL/6J mice | HK-2 | — | regulate TIMP1 | regulate tubular basement membrane thickening, collagen deposition, and albuminuria | (109) |
| SIRT6 | STZ-induced diabetic rats | THP-1, MPC5 | — | upregulate Bcl2 and CD206, decrease Bax and CD86 | activate M2 macrophages regulating immune response, protect podocyte injury | (110) |
| SIRT6 | db/db mice | HK-2 | — | Smad3 deacetylation | regulate tubular injury and renal function loss | (111) |
| SIRT6 | STZ-induced Kunming mice | Rat MC | — | regulate IL6, IL1β, TNFα and MPO | regulate proliferation, migration, fibrosis and inflammatory response in mesangial cells | (112) |
| SIRT6 | STZ-induced diabetic rats | mouse PTC | — | affect nuclear translocation of FoxO1 | reverse the glucose reabsorption and gluconeogenesis effect | (113) |
GEC, Glomerular endothelial cells; VSMC, vascular smooth muscle cells; CIP, conditionally immortalized podocytes; MC, mesangial cells; PTC, proximal tubular cells. Specific cell lines: HUVEC, human umbilical vein endothelial cells; MPC5, mouse podocyte cells; SV40 MES13, mouse mesangial cell line; NRK-52E, rat renal tubular epithelial cells; HK-2, human tubular epithelial cells; HEK293, HEK293A, HEK293T, human embryonic kidney cells; THP-1, human peripheral blood monocyte; RAW 264.7, mouse macrophage-like cell line. Special treatment: streptozotocin (STZ), high-fat diet (HFD), OLETF rats, OVE26 mice, db/db mice, BTBR ob/ob mice and Akita mice were seen in the main body of text.