Table 2.
Examples of potential mechanisms underlying renal benefits of drugs with antiaging effects.
| Drugs | Beneficial effects | Mechanisms | In vivo | In vitro | Ref. |
|---|---|---|---|---|---|
| Resveratrol | Attenuation of renal fibrosis | Regulation of AMPK/NOX4/ROS signaling | db/db mice | [255] | |
| Resveratrol | Renoprotection | Enhancement of hypoxia-induced autophagy via Sirt1 | STZ-induced diabetic rats, | Hypoxic-condition-induced rat proximal tubular epithelial cells NRK-52e | [110] |
| Resveratrol | Suppression of renal inflammation and mesangial cell proliferation | Modulation on Akt/NF-𝜅B pathway | STZ-induced diabetic rats; | HG-induced rat mesangial cells | [256] |
| Resveratrol | Regulating oxidative stress and mitochondrial function | Modulation of the Sirt1/FoxO1 signal pathway | STZ-induced diabetic rats | HG-induced rat mesangial cells | [165, 257] |
| Resveratrol | Renoprotection | Extenuating the oxidative stress and downregulation of RAGE expression | STZ-induced diabetic rats | [258] | |
| Resveratrol | Ameliorating lipotoxicity, oxidative stress, apoptosis, endothelial dysfunction; glomerular matrix expansion and inflammation | Activating the AMPK-Sirt1-PGC-1α axis and PPARα through increases in AdipoR1 and AdipoR2 expression | db/db mice | HG-induced human glomerular endothelial cells and NMS2 mesangial cells | [259, 260] |
| Resveratrol | Protection on podocytes | Activation of autophagy involved with miR-383-5p | db/db mice | HG-induced human podocytes | [261] |
| Resveratrol | Protection on mesangial cells | Negative regulation of the p38 MAPK/TGF-β1 pathway | STZ-induced diabetic rats | HG-induced rat mesangial cells | [167] |
| Resveratrol | Protection on podocytes | Against apoptosis by increasing autophagy via miRNA-18a-5p expression | db/db mice | HG-induced human podocytes | [262] |
| Resveratrol | Effect on endoplasmic reticulum stress | Reducing expressions of 78 kDa glucose-regulated protein (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) | STZ induced diabetic rats | [263] | |
| Resveratrol | Protection on podocytes | Reducing oxidative damage and apoptosis of podocytes via Sirt1/PGC-1α mitochondrial protection | HG-induced immortalized mouse podocytes | [164] | |
| Resveratrol | Renoprotection and reducing albuminuria | Suppression of the angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) axis and enhancing the angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis; anti-inflammation and oxidative stress | Aged C57BL/6 mice | [30] | |
| Resveratrol | Regulation on endothelial dysfunction | Modulation of Sirt1 and PPARγ | db/db mice | [166] | |
| Metformin | Restore the insulin responsiveness of podocytes | Regulating Sirt1 and AMPK activities | HG-induced rat podocytes | [182] | |
| Metformin | Exhibiting an anti-apoptotic impact on podocytes | Activation of AMPK and inhibition of mTOR signaling | HG-induced immortalized human podocytes | [178] | |
| Metformin | Renoprotective effect | Increasing SOD activity and decreasing malondialdehyde level; decreasing the expression levels of TGF-β1 | STZ-induced diabetic rats | [264] | |
| Metformin | Improving diabetic tubulopathy | Increasing in PGC1α activity by modulating mitochondrial dynamics and autophagy | STZ-induced diabetic mice, | HG-induced human renal proximal tubular epithelial cell line HKC8 | [188] |
| Metformin | Against proteinuria cytotoxicity | Suppression of Akt and mTOR activation, inhibition of EMT and apoptosis and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms | Albumin-induced rat renal proximal tubular cells | [187] | |
| Metformin | Protection on podocytes | Upregulating the renal tissue nephron expression | STZ-induced rats | [180] | |
| Metformin | Protection on podocytes | Increases extracellular ATP concentration, leading to activation of P2 receptors and consequent modulation of the podocytes' metabolism through AMPK and NAD(P)H oxidase | HG-induced mouse podocytes | [179] | |
| Metformin | Alleviation of cell senescence | Downregulation of Connexin43 via activation of AMPK and the inhibition of mTOR | HG-induced primary rat glomerular mesangial cells | [189] | |
| Metformin | Alleviation of high-glucose-induced oxidative stress | Regulating p-p38MAPK protein expression | HG-induced rat glomerular mesangial cells | [265] | |
| Metformin | Alleviation of inflammation | Inhibits nuclear factor-κB activation and inflammatory cytokines expression including monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular depend on AMPK | HG-induced rat glomerular mesangial cells | [183] | |
| Metformin | Inhibition of apoptosis and inflammatory and fibrotic reactions in tubular cells | Reducing ROS generation via suppression of RAGE expression through AMP-activated protein kinase activation | AGEs induced human proximal tubular epithelial cells | [266] | |
| Metformin | Relieving oxidative stress, slowed down abnormal cell proliferation | Enhancing autophagy and through Sirt1/FoxO1 pathway via AMPK | STZ-induced diabetic rats; | HG-induced rat mesangial cells, | [185, 186] |
| Metformin | Exerting anti-inflammatory | Upregulating GLP-1R expression via AMPK | db/db mice | HG-induced rat mesangial cell line (HBZY-1) | [184] |
| Metformin | Attenuating hypoxia | Reducing uncoupling protein-2- (UCP2-) mediated mitochondrial proton LEAK | STZ-induced diabetic rats | [267] | |
| Metformin | Alleviating cell senescence | Reducing p21 expression by activating AMPK. | Human embryonic kidney (HEK293) cell line | [190] | |
| Metformin | Improving epithelial-to-mesenchymal transition | Inhibiting early growth response- (Egr-) 1; inhibiting MCP-1 expression via BMP and activin membrane-bound inhibitor- (BAMBI-) mediated inhibition of ERK1/2 | TGF-β1-induced rat renal tubular epithelial cell line (NRK-52E) | [268, 269] | |
| GLP-1 | Protection of podocytes | Against apoptosis, inhibition reactive oxygen species production and proinflammatory cytokine secretion, through Sirt1 activation | HG-induced mouse podocytes | [197] | |
| GLP-1R agonist (Exendin-4) | Against renal fibrosis | Inhibiting the transfer of extracellular vesicle miR-192 | HG-induced renal tubular epithelial cells | [270] | |
| GLP-1R agonist (Exendin-4) | Inhibiting cell proliferation and fibronectin secretion | Reversing ERK phosphorylation and enhancing expression of mTOR via AMPK | HG-induced rat mesangial cells | [271] | |
| GLP-1 analog (liraglutide) | Against renal inflammatory and protection on endothelial cells | Inhibiting STAT3/JAK2 expression via SIRT1 | db/db mice | AGEs- or HG-induced endothelial cells | [272] |
| GLP-1R analog (liraglutide) | Ameliorating early renal injury | Increasing the expression of FoxO1 mRNA and reducing renal phosphorylation levels of Akt and FoxO1 protein | STZ-induced diabetic rats | [273] | |
| GLP-1R analog (liraglutide) | Renoprotective effect | Inhibiting autophagy and apoptosis dependent on GLP-1R | HG-induced human renal tubular epithelial cell line (HK-2) | [274] | |
| GLP-1 analog (liraglutide) | Against oxidative stress and albuminuria | Via a PKA-mediated inhibition of renal NAD(P)H oxidase | STZ-induced diabetic rats | HG-induced human mesangial cells | [275] |
| DPP 4 inhibitor (sitagliptin) | Attenuation of glomerular lesions | Alleviation of oxidative injury | STZ-induced diabetic rats | [276] | |
| SGLT2i (dapagliflozin) | Attenuation of renal fibrosis | Elevating O-GlcNAcylation and tubular hypoxia | STZ-induced diabetic rats | HG-induced human proximal tubular epithelial cell line (HK-2) | [277] |
| SGLT2i (dapagliflozin) | Against inflammation and postponing the progression of renal injury | Inhibition of HMGB1-RAGE-NF-κB signaling pathway | HG-induced human proximal tubular epithelial cell line (HK-2) | [278] | |
| SGLT2i (canagliflozin) | Against renal inflammation, extracellular matrix turnover and fibrosis | Reduction in TNFR1, IL-6, MMP7 and FN1 | HG-induced human proximal tubular epithelial cell line (HK-2) | [279] | |
| SGLT2i (Ipragliflozin) | Improvements in glomerular damage | Normalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stress | db/db mice | [280] | |
| SGLT2i (Empagliflozin) | Anti-inflammatory and antifibrotic effects | Suppressing AGE-RAGE axis | STZ-induced diabetic rats | [281] | |
| Pioglitazone | Reprotection in DM | Decreasing expression of hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) | STZ-induced diabetic rats | [282] | |
| Pioglitazone | Ameliorating aging-related renal injury | Increasing klotho, decreasing oxidative stress, and mitochondrial injury; regulating p66Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C | Aging male Sprague-Dawley rats | [201] | |
| Dasatinib and quercetin | Decreasing human senescent cell burden | Alleviating adipose tissue senescent cell burden, decreasing skin epidermal p16INK4A+ and p21CIP1+ cells and circulating SASP factors in patients with DN | Human tissues | [216] |
Abbreviations: STZ: streptozotocin; DN: diabetic nephropathy; HG: high glucose; GLP-1: glucagon-like peptide-1; DPP4: dipeptidyl peptidase 4; SGLT2i: sodium-glucose cotransporter-2 inhibitor; AMPK/NOX4/ROS: AMP-activated protein kinase/NADPH oxidase-4/reactive oxygen species; Akt/NF-κB: protein kinase B/nuclear factor kappa-B; FoxO1: forkhead box O 1; PGC-1: peroxisome proliferator-activated receptor- (PPAR-) α coactivador-1; AdipoR: adiponectin receptor protein; MAPK: mitogen-activated protein kinase; TGF-β: transforming growth factor-β: mTOR: mammalian target of rapamycin; SOD: superoxide dismutase; EMT: epithelial-mesenchymal transdifferentiation; RAGE: receptor for advanced glycation end products (AGEs); HMGB1: high mobility group box 1-receptor; ERK: extracellular signal-regulated kinase; STAT3: signal transducer and activator of transcription; JAK2: janus kinase 2; TNFR1: TNF receptor 1; MMP7: matrix metalloproteinase 7; FN1: fibronectin 1.