Kaempferol inhibits renal fibrosis by suppression of the sonic hedgehog signaling pathway

Yiqing Guan; Dongling Quan; Kai Chen; Liangqi Kang; Danni Yang; Huanxian Wu; Mengqiu Yan; Shaoyu Wu; Lin Lv; Guohua Zhang

doi:10.1016/j.phymed.2022.154246

Kaempferol inhibits renal fibrosis by suppression of the sonic hedgehog signaling pathway

Phytomedicine. 2023 Jan:108:154246. doi: 10.1016/j.phymed.2022.154246. Epub 2022 Jun 6.

Authors

Yiqing Guan¹, Dongling Quan², Kai Chen¹, Liangqi Kang¹, Danni Yang², Huanxian Wu², Mengqiu Yan², Shaoyu Wu², Lin Lv³, Guohua Zhang⁴

Affiliations

¹ School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510000, China.
² School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510000, China.
³ School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510000, China. Electronic address: lynnlv@smu.edu.cn.
⁴ School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510000, China. Electronic address: zghgz@163.com.

PMID: 36274411
DOI: 10.1016/j.phymed.2022.154246

Abstract

Background: Most chronic kidney diseases (CKDs) develop to end-stage renal disease (ESRD), which is characterized by fibrosis and permanent tissue and function loss. As a result, better and more effective remedies are essential. Kaempferol (KAE) is a common flavonoid extracted from plants. It can control the progression of kidney fibrosis and the epithelial-to-mesenchymal transition (EMT) of the renal tubular system.

Purpose: We aim to investigate the effect of KAE therapy on extracellular matrix deposition and stimulation of EMT in vitro and in vivo to elucidate the treatment mechanisms regulating these effects.

Study design: Chronic hypertension-induced kidney fibrosis was studied in spontaneously hypertensive rats with chronic kidney disease. Biochemical analysis, histological staining, and the expression level of relative proteins were used to assess the effect of KAE on renal function and fibrosis. The direct impact of KAE on proliferation and migration was evaluated using human renal tubular epithelial cells (HK-2) induced by transforming growth factor-β1 (TGF-β1), which can then induce EMT. The molecular mechanism of KAE was verified using co-IP assay and immunofluorescence.

Results: KAE could reduce blood pressure and decrease the extracellular matrix (ECM) components (including collagen I and collagen Ш), TGF-β1, and α-SMA in the kidneys of hypertension-induced rats with chronic kidney disease. Moreover, in HK-2 cell treated with TGF-β1, KAE administration significantly suppressed proliferation, migration, and EMT via increasing the expression of E-cadherin, while reducing the N-cadherin and α-SMA. Sufu was exceedingly repressed in HK-2 cells treated with TGF-β1. KAE inhibited the activation of Shh and Gli through increasing the expression of Sufu, thereby blocking the nuclear translocation of Gli1 in vitro.

Conclusion: KAE ameliorated kidney fibrosis and EMT by inhibiting the sonic hedgehog signaling pathway, thereby to attenuate the pathological progression of hypertensive kidney fibrosis.

Keywords: Epithelial-to-mesenchymal transition; Kaempferol; Kidney fibrosis; Sonic hedgehog signaling pathway.

MeSH terms

Animals
Collagen
Epithelial-Mesenchymal Transition
Fibrosis
Hedgehog Proteins / metabolism
Humans
Hypertension* / complications
Kaempferols* / pharmacology
Rats
Renal Insufficiency, Chronic* / drug therapy
Renal Insufficiency, Chronic* / etiology
Transforming Growth Factor beta1 / metabolism

Substances

Collagen
Hedgehog Proteins
Kaempferols
Transforming Growth Factor beta1