A recent study showed that phosphatase and tension homologue (PTEN)-induced kinase 1/ (PINK1)/mitofusion 2 (MFN2)/Parkin-mediated macrophage mitophagy is downregulated during kidney fibrosis, and loss of either Pink1 or Parkin promoted macrophage development toward profibrotic/M2 macrophages and subsequent renal fibrosis
[50]. Additionally, autophagy induced by the histone deacetylase inhibitor, valproic acid, suppressed renal fibrosis in mice subjected to UUO
[51]. Taken together, these studies support that autophagy suppresses renal fibrosis in obstructed kidneys and may provide a pro-survival role (). Rubicon, a negative regulator of autophagy, increased during aging, suppressed autophagic activity, and caused fibrosis in mouse kidney and α-Syn accumulation in mouse brain
[52]. In streptozotocin (STZ)-induced diabetic nephropathy in rats, microRNA (miR)-22 upregulation was associated with increased fibrosis and suppression of autophagy
[53]. In normal rat kidney (NRK)-52E cells, rapamycin-induced autophagy reduced high glucose-induced collagen IV (Col IV), and
α–smooth muscle actin (
α-SMA) expression and overexpression of miR-22 suppressed autophagic flux and induced the expression of Col IV and
α-SMA
[53]. Also, triptolide (TP), a traditional Chinese medicine, reduced fibrosis by increasing autophagy via the miR-141-3p/PTEN/protein kinase B (Akt)/mTOR pathway in STZ-induced diabetic nephropathy in high fat diet (HFD)-fed rats
[54]. 1,25-dihydroxyvitamin D3 ameliorated Ang II-induced tubulointerstitial fibrosis, expanded mesangial regions and foot process fusion, and impaired autophagy by improving mitochondrial dysfunction and by modulating autophagy
[55]. Elafibranor, a novel dual peroxisome proliferator-activator receptor
α/
δ (PPAR
α/
δ) agonist, protected HFD mice with CKD by improving kidney-specific protective effects, including preservation of glomerular/tubular barrier protein, maintenance of the structure, antioxidative stress, and activation of sirtuin (SIRT)-autophagy
[56]. Postconditioning (POC) following IR injury reduced renal damage and renal fibrosis by increased autophagy
[57].
Periostin gene
, also known as osteoblast-specific factor-2 that plays a role as a profibrotic and proinflammatory factor
[58], is upregulated in kidneys with 5-6 nephrectomy and impaired autophagy flux. Knockdown of
periostin afforded protection against 5/6 nephrectomy-induced intrarenal renin-angiotensin system activation, fibrosis, inflammation in rats, and improved autophagy flux
[59], suggesting that
periostin-induced impaired autophagy is involved in the inflammation and fibrosis in the profibrotic model. In contrast, other studies have recently shown that the induction of autophagy results in renal fibrosis. Persistent activation of autophagy during UUO promoted renal interstitial fibrosis, macrophage infiltration, and tubular atrophy
[60]. Proximal tubule-specific deletion of
Atg7 suppressed tubular atrophy, nephron loss, interstitial macrophage infiltration, interstitial fibrosis, and expression of the profibrotic factor fibroblast growth factor 2 (FGF2)
[60]. Furthermore, a Chinese herb rhubarb and its bioactive component rhein that improved renal function and the glomerular filtration rate (GFR) in stage 3 and 4 patients with CKD
[61] inhibited autophagy. Protein kinase Cα (PKCα) is activated during UUO fibrotic kidney, and inhibition of PKCα blocked autophagic flux in fibroblasts of the fibrotic kidneys and prevented fibroblast activation and kidney fibrosis
[62]. Rhubarb also suppressed renal fibrosis
[63]. These studies are summarized in . In view of the above results, additional studies with different experimental models of renal fibrosis are required using both genetic and pharmacological approaches to better understand the definitive role of autophagy in renal interstitial fibrosis.
Table 1. Autophagy in renal interstitial fibrosis.
Kidney Disease |
Agent/Drug |
Effect on Autophagy |
Effect on Fibrosis |
Reference |
Autophagy suppresses fibrosis |
UUO model |
3-MA |
↓ autophagy |
↑ in interstitial fibrosis and tubular apoptosis |
[42][43][44][42,43,44] |
LC3 KO and beclin-1 ± |
↓ autophagy |
↑ deposition of collagen and TGF-β1 |
[46] |
Conditional deletion of ATG7 in distal tubule |
↓ autophagy in the distal tubules |
↑ in tubulointerstitial fibrosis via the TGF-β/Smad4 and NLRP3 signaling |
[47] |
Conditional deletion of ATG5 |
↓ autophagy |
↑ renal interstitial fibrosis and cell cycle arrest at G2/M |
[48] |
Proximal tubule specific deletion of ATG5 |
↓ autophagy |
↑ renal fibrosis due to leukocyte infiltration and expression of pro-inflammatory cytokines |
[49] |
Valproic acid (histone deacetylase inhibitor) |
↑ autophagy |
↓ in renal fibrosis |
[51] |
Rubicon |
↓ autophagy |
↑ in renal fibrosis |
[52] |
STZ- DN |
miR -22 upregulation |
↓ autophagy |
↑ in renal fibrosis with increased expression of col-IV and α-SMA |
[53] |
Triptolide |
↑ autophagy via miR-141-3p/PTEN/Akt/mTOR pathway |
↓ in renal fibrosis |
[54] |
HFD with CKD |
Elafibranor (dual PPARα/δ agonist) |
↑ autophagy mediated by SIRT1 |
↓ in renal fibrosis |
[56] |
5/6-Nephrectomy |
Knockdown of periostin gene (osteoblast specific factor-2) |
↑ autophagy and upregulates periostin gene (pro-fibrotic and pro-inflammatory factor) |
↓ in renal inflammation and fibrosis |
[58] |
Proximal tubule specific deletion of ATG7 |
↑ autophagy |
↓ in renal fibrosis with pro-fibrotic FGF2 |
[60] |
Autophagy promotes fibrosis |
Ang II- induced CKD |
1,25-dihydroxyvitamin D3 |
↓ autophagy with improved mitochondrial dysfunction |
↓ in renal fibrosis |
[55] |
Stage 3 and stage 4 CKD |
Rhubarb (Rhein- bioactive component) |
↓ autophagy |
↓ in renal fibrosis |
[61] |