Effect of Shenkang on renal fibrosis and activation of renal interstitial fibroblasts through the JAK2/STAT3 pathway

Tianyu Qin,Lili Wu,Tonghua Liu,You Wu

doi:10.1186/s12906-020-03180-3

Tianyu Qin, Lili Wu + Show 2 more

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https://doi.org/10.1186/s12906-020-03180-3

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Abstract

BackgroundActivation of renal fibroblasts is a critical mechanism in the process of renal fibrosis. As a commonly used herbal formula, Shenkang (SK) has been found to attenuate renal fibrosis and renal parenchyma destruction. However, the effect of SK on renal fibroblast activation in unilateral ureteral obstruction (UUO) mice and its molecular mechanism remain undetermined. The present study was performed to elucidate the effect of SK on renal fibroblast activation and renal fibrosis, as well as the potential underlying mechanism, in both NRK-49F cells and UUO mice.MethodsNRK-49F cells were stimulated with 10 ng/ml TGF-β1 for 48 h. After SK treatment, the CCK-8 method was used to evaluate cell viability. Thirty-six C57BL/6 mice were randomly divided into the sham group, UUO group, angiotensin receptor blocker (ARB) group, and SK high-, moderate- and low-dose groups. UUO was induced in mice except those in the sham group. Drugs were administered 1 day later. On the 13th day, the fractional anisotropy (FA) value was determined by MRI to evaluate the degree of renal fibrosis. After 14 days, serum indexes were assessed. Hematoxylin and eosin (HE) and Sirius red staining were used to observe pathological morphology and the degree of fibrosis of the affected kidney. Western blotting and PCR were used to assess the expression of related molecules in both cells and animals at the protein and gene levels.ResultsOur results showed that SK reduced extracellular matrix (ECM) and α-smooth muscle actin (α-SMA) expression both in vitro and in vivo and attenuated renal fibrosis and the pathological lesion degree after UUO, suppressing JAK2/STAT3 activation. Furthermore, we found that SK regulated the JAK2/STAT3 pathway regulators peroxiredoxin 5 (Prdx5) in vitro and suppressor of cytokine signaling protein 1 (SOCS1) and SOCS3 in vivo.ConclusionsThese results indicated that SK inhibited fibroblast activation by regulating the JAK2/STAT3 pathway, which may be a mechanism underlying its protective action in renal fibrosis.

Highlights

Activation of renal fibroblasts is a critical mechanism in the process of renal fibrosis
We further demonstrated that these curative effects of SK may have been achieved by targeting the JAK2/STAT3 pathway in cultured NRK-49F cells and a ureteral obstruction (UUO) mouse model
To further investigate whether SK could suppress the activation of renal interstitial fibroblasts, we examined the effect of SK on α-smooth muscle actin (α-SMA) and collagen Collagen III (III) expression in NRK-49F cells

Summary

Introduction

Activation of renal fibroblasts is a critical mechanism in the process of renal fibrosis. The present study was performed to elucidate the effect of SK on renal fibroblast activation and renal fibrosis, as well as the potential underlying mechanism, in both NRK-49F cells and UUO mice. The primary pathological process of renal injury leads to normal renal parenchyma destruction and progressive scar tissue formation, which leads to fibrosis. Renal tubulointerstitial fibrosis is the typical pathway for the progressive development of almost all CKDs and the main pathological basis for end-stage renal disease, which is characterized by tubular epithelial cell atrophy, inflammatory cell infiltration, aberrant activation and growth of renal fibroblasts and excessive extracellular matrix (ECM) accumulation [4, 5]. The activation of interstitial fibroblasts into myofibroblasts could help repair damaged tissue. When this repair process is abnormal and excessive ECM is secreted, irreversible kidney damage results. The signaling pathway that mediates myofibroblast activation may be a target for alleviating the process of renal fibrosis

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