Keywords
Renal interstitial fibrosis
Sonic hedgehog
Serum biomarker
Kidney biopsy specimens
Submitted : 2026-06-07
Accepted : 2026-06-22
Published : 2026-07-07
Abstract
Background: Sonic hedgehog (SHH) has been found to be involved in chronic kidney disease (CKD) development. Aims: This study aims to explore the clinical significance of SHH in renal interstitial fibrosis (RIF) of CKD patients. Methods: SHH serum levels were determined using enzyme-linked immunosorbent assays. Expressions of SHH, TGF-β and CTGF in kidney biopsy specimens of CKD patients were measured by immunohistochemistry staining. Results: Serum levels of SHH were significantly higher in stage 3–4 and stage 5 of CKD patients than that in healthy controls. SHH levels were positively correlated with Scr, BUN and UA levels; negatively correlated with HGB and eGFR in CKD patients. SHH was the risk factor for DKD. In addition, The expression of SHH was significantly increased in stage 3–4 patients compared to stage 1–2 patients, and increased in severe interstitial fibrosis group than that in the mild interstitial fibrosis group. SHH expression was positively correlated with renal interstitial fibrosis score and profibrotic factors (TGF-β and CTGF) in CKD patients. Conclusions: SHH might serve as a potential biomarker for CKD and mediate the pathogenesis of RIF in CKD patients.
References
Schnaper H, 2014, Remnant Nephron Physiology and the Progression of Chronic Kidney Disease. Pediatric Nephrology, 29(2): 193–202.
Zhong J, Yang H, 2017, A Perspective on Chronic Kidney Disease Progression. American Journal of Physiology-Renal Physiology, 312(3): F375–F384.
Kiuchi M, Mion D, 2016, Chronic Kidney Disease and Risk Factors Responsible for Sudden Cardiac Death: A Whiff of Hope? Kidney Research and Clinical Practice, 35(1): 3–9.
Liu B, Tang T, Lv L, et al., 2018, Renal Tubule Injury: A Driving Force Toward Chronic Kidney Disease. Kidney International, 93(3): 568–579.
Koo J, 2006, Renal Interstitial Fibrosis and Angiotensin Inhibition. Electrolyte & Blood Pressure, 4(1): 35–43.
Farris A, Colvin R, 2012, Renal Interstitial Fibrosis: Mechanisms and Evaluation. Current Opinion in Nephrology and Hypertension, 21(3): 289–300.
Liu B, Tang T, Lv L, 2019, How Tubular Epithelial Cell Injury Contributes to Renal Fibrosis. Advances in Experimental Medicine and Biology, 1165: 233–252.
Qi R, Yang C, 2018, Renal Tubular Epithelial Cells: The Neglected Mediator of Tubulointerstitial Fibrosis After Injury. Cell Death & Disease, 9(11): 1126.
Robbins D, Fei D, Riobo N, 2012, The Hedgehog Signal Transduction Network. Science Signaling, 5(246): re6.
Varjosalo M, Taipale J, 2007, Hedgehog Signaling. Journal of Cell Science, 120(Pt 1): 3–6.
Liu F, Feng X, Zhu S, et al., 2018, Sonic Hedgehog Signaling Pathway Mediates Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via MAPK/ERK Signaling Pathway. Frontiers in Immunology, 9: 2847.
Saldaña J, Solanki A, Lau C, et al., 2016, Sonic Hedgehog Regulates Thymic Epithelial Cell Differentiation. Journal of Autoimmunity, 68: 86–97.
Liu P, Chen L, 2018, Inhibition of Sonic Hedgehog Signaling Blocks Cell Migration and Growth but Induces Apoptosis via Suppression of FOXQ1 in Natural Killer/T-Cell Lymphoma. Leukemia Research, 64: 1–9.
Zhou S, Ai Z, Li W, et al., 2020, Shenkang VII Recipe Attenuates Unilateral Ureteral Obstruction-Induced Renal Fibrosis via TGF-β/Smad, NF-κB and SHH Signaling Pathway. Current Medical Science, 40(5): 917–930.
Bai Y, Lu H, Lin C, et al., 2016, Sonic Hedgehog-Mediated Epithelial-Mesenchymal Transition in Renal Tubulointerstitial Fibrosis. International Journal of Molecular Medicine, 37(5): 1317–1327.
Zhou D, Li Y, Zhou L, et al., 2014, Sonic Hedgehog Is a Novel Tubule-Derived Growth Factor for Interstitial Fibroblasts After Kidney Injury. Journal of the American Society of Nephrology, 25(10): 2187–2200.
Ding H, Zhou D, Hao S, et al., 2012, Sonic Hedgehog Signaling Mediates Epithelial-Mesenchymal Communication and Promotes Renal Fibrosis. Journal of the American Society of Nephrology, 23(5): 801–813.
Madić V, Petrović A, Jušković M, et al., 2021, Polyherbal Mixture Ameliorates Hyperglycemia, Hyperlipidemia and Histopathological Changes of Pancreas, Kidney and Liver in a Rat Model of Type 1 Diabetes. Journal of Ethnopharmacology, 265: 113210.
Xue M, Yang F, Le Y, et al., 2021, Klotho Protects Against Diabetic Kidney Disease via AMPK- and ERK-Mediated Autophagy. Acta Diabetologica, 58(10): 1413–1423.
Li Y, Wen X, Liu Y, 2012, Tubular Cell Dedifferentiation and Peritubular Inflammation Are Coupled by the Transcription Regulator Id1 in Renal Fibrogenesis. Kidney International, 81(9): 880–891.
Grande M, Sánchez-Laorden B, López-Blau C, et al., 2015, Snail1-Induced Partial Epithelial-to-Mesenchymal Transition Drives Renal Fibrosis in Mice and Can Be Targeted to Reverse Established Disease. Nature Medicine, 21(9): 989–997.
Kang H, Ahn S, Choi P, et al., 2015, Defective Fatty Acid Oxidation in Renal Tubular Epithelial Cells Has a Key Role in Kidney Fibrosis Development. Nature Medicine, 21(1): 37–46.
Lovisa S, LeBleu V, Tampe B, et al., 2015, Epithelial-to-Mesenchymal Transition Induces Cell Cycle Arrest and Parenchymal Damage in Renal Fibrosis. Nature Medicine, 21(9): 998–1009.
Zhou D, Tan R, Liu Y, 2016, Sonic Hedgehog Signaling in Kidney Fibrosis: A Master Communicator. Science China Life Sciences, 59(9): 920–929.
Fabian S, Penchev R, St-Jacques B, et al., 2012, Hedgehog-Gli Pathway Activation During Kidney Fibrosis. American Journal of Pathology, 180(4): 1441–1453.
Zhou D, Fu H, Liu S, et al., 2019, Early Activation of Fibroblasts Is Required for Kidney Repair and Regeneration After Injury. FASEB Journal, 33(11): 12576–12587.