Hydroxychloroquine relieves renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway

CKD is a worldwide public health problem with an adult prevalence of about 13.
4%.

Renal interstitial fibrosis is a key predictor of progressive CKD and is considered a superior predictor of progression compared with eGFR
.
Tubulointerstitial fibrosis is characterized by excessive accumulation and deposition of the extracellular matrix (ECM), ultimately leading to progressive loss
of end-stage renal disease (ESRD) of renal function.
However, there is no effective treatment solution to slow the development of
renal fibrosis.
Therefore, there is an urgent clinical need for safe and effective drugs to treat the progression
of renal fibrosis.
Hydroxychloroquine (HCQ) has been shown to have anti-inflammatory and immunomodulatory effects
.
Recently, researchers have discovered that HCQ can attenuate pulmonary fibrosis by inhibiting NF-kB and ERK1/2 signaling pathways.

However, the exact molecular mechanism of HCQ in the treatment of renal fibrosis is unknown
.

In this study, the investigators systematically elucidated the potential mechanism
of action of HCQ in renal fibrosis by combining network pharmacology and bioinformatics.
First, network pharmacology was used to elucidate the potential target genes
of HCQ for the treatment of renal fibrosis.
In addition, network-based pharmacology was investigated whether HCQ may inhibit the progression of renal fibrosis via the PI3K/AKT signaling pathway and validated
by in vivo and in vitro experiments.
Moreover, HCQ was also found to reduce the release of inflammatory factors and apoptosis during renal fibrosis
.

Network pharmacology elucidates HCQ potential targets and signaling pathways in renal fibrosis:

Methods: C57BL/6J mice are randomized into three groups (pseudogroup, UUO group, and UUO+HCQ group (20 mg/kg)).

HE and Masson stains were performed to assess renal tissue damage and fibrosis, and western blot was used to assess the expression
of epithelial-mesenchymal transformation (EMT), extracellular matrix (ECM), PI3K/AKT, and NF-κB-associated proteins.
PCR and TUNEL were used to detect inflammatory factors and apoptosis
.
HK-2 cells treated with TGF-β1 are used for in vitro experiments
.

HCQ relieves fibrosis in vivo and in vitro experiments:

Results: HCQ may have potential therapeutic effects on renal fibrosis mediated by 122 target genes, and the Kyoto Gene Encyclopedia based on network pharmacology and genomic pathways of these genes are enriched for PI3K/AKT signaling
.
UUO mice receiving HCQ showed much less tubular damage
than UUO mice.
HCQ treatment also dulls EMT and TGF-β1-treated tubular epithelial cells in UUO kidneys and mitigates the deposition
of ECM in kidney tissue.
In addition, HCQ treatment reduced UUO-induced inflammation and apoptosis
.
Mechanically, HCQ processing inhibits the activation of the
PI3K/Akt and NF-kB pathways.

HCQ reduces apoptosis and inflammatory processes in the UUO kidneys:

In summary, the investigators first elucidated hydroxychloroquine to alleviate renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway based on network pharmacology, and verified
it experimentally.
In addition, HCQ also attenuates renal fibrosis and EMT processes by inhibiting the NF-KB pathway and modulating the immune inflammatory response and apoptosis, ultimately improving kidney damage
in UOO-induced CKD mice.
This study provides a basis
for HCQ in the treatment of renal fibrosis and the management and prevention of CKD.
However, further research is needed to verify the safety and efficacy
of HCQ in the treatment of renal fibrosis.

References: Li D, Yu K, Feng F, Zhang Y, Bai F, Zhang Y, Sun N, Fan J, Liu L, Yang H, Yang X.
Hydroxychloroquine alleviates renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway.
Biochem Biophys Res Commun.
2022 Jun 25; 610:154-161.
doi: 10.
1016/j.
bbrc.
2022.
04.
058.
Epub 2022 Apr 15.
PMID: 35462097.