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Published on: May 10, 2022
Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192
Lin Sun1, Dongshan Zhang, Fuyou Liu
1Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. sunlinnwu11@163.com
Abstract:
Transforming growth factor (TGF)-β has been shown to play a central role in the development of tubulointerstitial fibrosis, which can be corrected via treatment with paclitaxel. The biology of microRNA (miR) can be modulated by paclitaxel. We hypothesized that paclitaxel may attenuate renal fibrosis in a rat model of remnant kidney disease by inhibiting TGF-β induced-miRs. Rats in groups of 12 were subjected to 5/6 nephrectomy and received low-dose intraperitoneal injection of paclitaxel. Renal functions were assessed at 8 weeks. The TGF-β signalling cascade and ECM proteins were evaluated by real-time polymerase chain reaction (TRT-PCR) and immunofluorescence microscopy. Animals with remnant kidneys developed hypertension, which was not relieved with paclitaxel treatment. However, paclitaxel treatment resulted in dampening the proteinuric response, reduction in serum BUN, creatinine levels and urine protein : creatinine ratio and normalization of creatinine clearance. These effects were accompanied by the inhibition of Smad2/3 activation, attenuation of renal fibrosis and normalization of integrin-linked kinase (ILK), COL(I)A1, COL(IV)A2 and α-SMA expression. Also, paclitaxel down-regulated the expression of miR-192, miR-217 and miR -377, while miR-15 was up-regulated in the remnant kidney. In vitro, in tubular epithelial cells (NRK-52E), paclitaxel also inhibited TGF-β1-induced Smad2/3 activation and normalized ILK, COL(I)A1, COL(IV)A2 and α-SMA expression. Furthermore, ChIP analyses indicated that Taxol suppressed Smad3-mediated miR-192 transcriptional activity. Over-expression of miR-192 in NRK-52E mimicked the changes seen in the remnant kidney, while inclusion of miR-192 inhibitor in the culture medium blocked TGF-β1-induced COL(I)A1 and COL(IV)A2 expression, while ILK and α-SMA were unaffected. These data suggest that low-dose paclitaxel ameliorates renal fibrosis via modulating miR-192 pathobiology and TGF-β/Smad signalling.
Insights
Low-dose paclitaxel (Taxol) treatment reduces renal fibrosis in rats by modulating microRNA-192 (miR-192) and inhibiting TGF-β signaling. This study highlights paclitaxel
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Tubulointerstitial fibrosis is a key factor in chronic kidney disease progression.
- Transforming growth factor-beta (TGF-β) signaling plays a critical role in fibrosis development.
- MicroRNAs (miRs) are implicated in kidney disease pathogenesis and can be modulated by drugs like paclitaxel.
Purpose of the Study:
- To investigate if paclitaxel can attenuate renal fibrosis in a rat model of remnant kidney disease.
- To determine the role of TGF-β-induced microRNAs in paclitaxel's renoprotective effects.
- To elucidate the molecular mechanisms underlying paclitaxel's action on renal fibrosis.
Main Methods:
- A rat model of 5/6 nephrectomy was used to induce remnant kidney disease.
- Rats received low-dose intraperitoneal paclitaxel, with renal function assessed at 8 weeks.
- TGF-β signaling, extracellular matrix (ECM) proteins, and specific microRNAs (miR-192, miR-217, miR-377, miR-15) were evaluated using RT-PCR and immunofluorescence.
- In vitro studies utilized NRK-52E tubular epithelial cells to confirm paclitaxel's effects on TGF-β1-induced signaling and miR-192 activity.
Main Results:
- Paclitaxel treatment improved renal function by reducing proteinuria, BUN, creatinine, and increasing creatinine clearance, despite not affecting hypertension.
- Paclitaxel inhibited Smad2/3 activation, attenuated renal fibrosis, and normalized the expression of integrin-linked kinase (ILK), COL(I)A1, COL(IV)A2, and α-SMA.
- Paclitaxel down-regulated miR-192, miR-217, and miR-377, while up-regulating miR-15. In vitro, paclitaxel suppressed Smad3-mediated miR-192 transcription, and miR-192 inhibition blocked TGF-β1-induced ECM expression.
Conclusions:
- Low-dose paclitaxel ameliorates renal fibrosis in a rat remnant kidney model.
- The renoprotective effects of paclitaxel are mediated through the modulation of miR-192 and inhibition of the TGF-β/Smad signaling pathway.
- Targeting miR-192 represents a potential therapeutic strategy for mitigating renal fibrosis.
