To determine the role of autophagy in renal fibrosis, most studies have used the unilateral ureteral obstruction (UUO) model
[42]; this model exhibits time-dependent induction of autophagy accompanied by tubular atrophy, tubular cell death, and interstitial fibrosis
[43][44]. The autophagy inhibitor 3-methyladenine (3-MA) enhanced tubular apoptosis and interstitial fibrosis in obstructed kidneys
[44]. In addition, transgenic mice with heterozygous deletion of beclin-1 (beclin-1 ± mice) showed increased deposition of type-1 collagen
[45]. LC3)-KO and beclin-1 ± mice subjected to the UUO model revealed increased deposition of collagen accompanied by increased levels of transforming growth factor (TGF)-β1 in the obstructed kidney
[46]. In this model, the induction of autophagy in distal tubular epithelial cells afforded protection from renal tubulointerstitial fibrosis through the regulation of the TGF-β/signal transducers and transcriptional modulator (Smad)4 signaling pathway and NOD-LRR and pyrin domain-containing protein3 (NLRP3) inflammasome/caspase-1/interleukin-1 β (IL-1β) signaling pathway
[47]. Conditional deletion of
Atg5 enhanced renal interstitial fibrosis and promoted cell cycle arrest at G2/M
[48]. It was shown that the deletion of
ATG5 in proximal tubular epithelial cells promoted leukocyte infiltration and expression of proinflammatory cytokines, while overexpression of ATG5 inhibited the inflammatory response in an autophagy-dependent manner via blocking nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) signaling that provides protection against renal inflammation and accompanied fibrosis
[49].
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.