TGF-β Inhibitors for Therapeutic Management of Kidney Fibrosis

Park, Cheol Ho; Yoo, Tae‐Hyun

doi:10.3390/ph15121485

Cited by 20 publications

(9 citation statements)

References 153 publications

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“…It includes several strategies including Smad agonists/inhibitors and neutralizing antibodies against receptors/cytokines. However, the pleotropic nature of this pathway has limited their application due to potential side effects [176].…”

Section: Hypoxia As a Therapeutic Target In Ckdmentioning

confidence: 99%

Hypoxia-Driven Responses in Chronic Kidney Disease

Miguel

Rojo

2023

Oxygen

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Chronic kidney disease (CKD) affects 10% of the population. Fibrosis is the hallmark of CKD, which is marked by the deposit of extracellular matrix (ECM). This response is the final outcome of an unbalanced reaction to inflammation and wound healing and can be induced by a variety of insults, including hypoxia. Vascular damage results in an impaired tissue oxygen supply, inducing immune cell infiltration, tubule injury and the activation of ECM-secreting myofibroblasts. In turn, tubulointerstitial fibrosis development worsens oxygen diffusion. Hypoxia-inducible factor (HIF) is the primary transcriptional regulator of hypoxia-associated responses, such as oxidative stress and metabolic reprogramming, triggering a proinflammatory and profibrotic landscape. In this review, we discuss hypoxia-driven reprogramming in CKD as well as potential therapeutic approaches to target chronic hypoxia.

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Section: Hypoxia As a Therapeutic Target In Ckdmentioning

confidence: 99%

Hypoxia-Driven Responses in Chronic Kidney Disease

Miguel

Rojo

2023

Oxygen

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“…Although PFD has been widely used to reduce pulmonary fibrosis [21], its effects remain largely unexplored in the renal field. Previous studies reported that PFD is a renoprotective agent that exerts its functions partly by inhibiting the TGF-beta signaling pathway [22,23]. Some studies also suggested that pirfenidone is a promising therapeutic agent for individuals with diabetic nephropathy [24].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Blockade of TGF-Beta Reduces Renal Interstitial Fibrosis in a Chronic Ischemia–Reperfusion Animal Model

Melo

Palomino

Franco-Acevedo

et al. 2023

DDC

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The targeting of transforming growth factor β (TGF-β) has been shown to reduce complications related to ischemia-reperfusion injury (IRI) post-surgically. Pirfenidone (PFD) specifically inhibits TGF-β expression and has been demonstrated to provide protection from IRI in short-term allograft models, though not yet in long-term models. A chronic unilateral IRI model was established using male Wistar rats. The animals were divided into two groups: one with IRI and a pre-treatment of PFD (0.5 mg/kg) followed by 0.5 mg/kg/day of orally administered PFD for 30 days, and a control group without PFD treatment. A sham group was also included. Kidneys and blood samples were collected after 30 days, and the renal function was evaluated by measuring the serum creatinine and KIM-1 levels. RT-PCR was used to analyze fibrosis-related genes, and Luminex to quantify the pro-inflammatory serum IL-18 cytokine. Renal section staining and histological analysis were used to detect collagen deposits. Comparison within the groups showed an increase in serum creatinine and KIM-1 expression after IRI in the control group, while PFD reduced COLL1A1 and TGF-β expression and demonstrated a reduction in fibrosis through histological stains. The treatment group also showed a reduction in IL-18. Our results suggest that PFD exerts protective effects on chronic renal IRI, reducing fibrosis development and inflammation. This study provides new insights into the treatment and management of chronic renal function loss after IRI.

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“…Readers are referred to recent reviews and reports on the therapeutic targeting of TGF-β in renal, pulmonary, liver, and cardiac fibrosis [ 4 , 370 , 371 , 372 , 373 ] for further information about the role of TGF-β in fibrosis.…”

Section: Role Of Tgf-βs In the Pathophysiology Of Fibrosismentioning

confidence: 99%

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

Danielpour

2024

Pharmaceuticals

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The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs’ pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies.

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TGF-β Inhibitors for Therapeutic Management of Kidney Fibrosis

Cited by 20 publications

References 153 publications

Hypoxia-Driven Responses in Chronic Kidney Disease

Hypoxia-Driven Responses in Chronic Kidney Disease

Pharmacological Blockade of TGF-Beta Reduces Renal Interstitial Fibrosis in a Chronic Ischemia–Reperfusion Animal Model

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

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