Kidney fibroblasts are integral for structural support and injury repair (Figure 1). Through interaction with other cells, they maintain tissue homeostasis and contribute to physiological functions like filtration and waste removal. For years, the scientific community neglected them until their role in chronic kidney diseases (CKD) was revealed. They have been recognized as the key mediators of fibrosis, the characteristic feature of CKD. Moreover, research has also found them associated with renal cell carcinoma. As a result, research on renal fibroblasts has grown substantially.
Kidney Fibroblasts
Kidney fibroblasts are located in the interstitial space between the capillaries and nephrons. They exhibit an elongated spindle-shaped morphology, and the ultrastructure study shows the presence of dense endoplasmic reticulum, granules comprising components of extracellular matrix (ECM), and extensions that connect to the basement membrane and other tissue cells such as endothelial cells, dendritic cells, and epithelial cells. They perform diverse functions essential for renal structure and functionality.
Functions of Kidney Fibroblasts
Extracellular Matrix (ECM) Production: They are responsible for the production of ECM components such as collagen, fibronectin, laminin, perlecan, etc. The ECM maintains the structural integrity of the kidneys, thus contributing to their physiological functions.
Erythropoiesis: A subpopulation of fibroblasts in the renal medulla and cortex also assumes an endocrine role and synthesizes erythropoietin, required for the formation of red blood cells (RBC). These erythropoietin-producing cells increase in number during anemic conditions. They possess dendritic morphology and markers- microtubule-associated protein 2 (MAP2) and neurofilament light (NF-L).
Supporting Tissue : In addition to structural support, fibroblasts assist cells like epithelial and endothelial cells in their functioning. For instance, they produce vascular endothelial growth factor (VEGF), which acts on endothelial cells to maintain the blood flow in the kidneys.
Injury Repair: Kidney injury triggers fibroblasts to stimulate the healing process. They proliferate and increase the synthesis of ECM. Research has demonstrated that the lack of fibroblasts can even aggravate the injury by affecting the cell proliferation.
Immune Regulation: At the time of injury, these cells also release chemokines and cytokines. These mediators recruit immune cells and modulate inflammation to prevent infection.
Blood Flow: They also express cyclooxygenase 1 (COX1) and COX2, the prostaglandin synthesis enzymes, thereby regulating the blood circulation in the kidneys.
Identification of renal fibroblasts
The kidney fibroblasts are mesenchymal-derived cells with identification markers cluster of differentiation 73 (CD73) and platelet-derived growth factor receptor β (PDGFRβ). However, pericytes in the kidneys also have mesenchymal origin and share similar markers as fibroblasts. Their anatomical locations can partly distinguish the two cells. But an accurate identification necessitates the combined assessment of location, shape, and markers of fibroblasts, along with the absence of certain markers that are present on other tissue cells, such as CD45, von Willebrand factor (vWF), smooth muscle 22 (SM22), etc.
Chronic Kidney Diseases (CKD)
CKD often results from kidney injury either caused by primary insults like acute kidney injury (AKI) or secondary insults via other diseases such as diabetes, infections, and cardiovascular disorders. It involves the progressive loss of nephrons and capillaries, marked by increased inflammation and oxidative stress. Advanced stages of CKD show complete renal failure, requiring replacement by dialysis or transplantation.
Research has divulged that Chronic Kidney Diseases (CKD) begins with tissue injury that triggers immune cell infiltration and fibroblast-dependent repair mechanisms. Fibrosis has been the underlying cause of the development and progression of CKD. During normal physiological conditions, fibroblasts produce ECM for reparative purposes. But repetitive injury dysregulates this process, leading to the generation of myofibroblasts and the subsequent initiation of fibrosis by excessive accumulation of ECM (Figure 2). It gradually spreads in the tissue, obstructing its normal functioning and deteriorating its structure, eventually resulting in total renal failure.
Renal Cell Carcinoma
Kidney fibroblasts have also been implicated in renal cell carcinoma. Cancer cells activate kidney fibroblasts, which, in turn, aid in cancer progression.
Immune Response: The activated fibroblasts alter the structural components and form an ECM-based barrier that prevents immune cell infiltration. They also regulate the tumor microenvironment (TME) to inhibit the immune cell activity.
Cell Proliferation: Fibroblasts promote tumor cell survival and proliferation. As the dependence of cancer cells on glucose decreases, fibroblasts induce lactic acid synthesis to support cancer cell growth. They also maintain the stemness of cancer stem cells and their subsequent progression into cancer. Through the development of the tumor-supporting niche, fibroblasts also enhance the resistance of cancer cells to chemotherapy.
Future Research on Kidney Fibroblasts
The mechanisms of kidney fibrosis are still not completely understood. The realization of fibroblast involvement in renal cell carcinoma has only been recent and requires further research. Consequently, research is ongoing on several aspects of renal fibroblasts.
Myofibroblast Formation:
Myofibroblast formation is a key step in the process of fibrosis. They have functional characteristics of smooth muscle cells helpful in the wound contraction. The α-smooth muscle actin (α-SMA) is a recognized marker of myofibroblasts. The cells that differentiate into myofibroblasts are not well-defined. Fibroblasts, pericytes, epithelial cells, and bone marrow-derived precursors are a few potential candidates for the origin of myofibroblasts. Although some studies have suggested fibroblasts to be the precursor of myofibroblasts, research in this field remains inconclusive.
Transition to Mesenchymal Cells:
Scientists have suggested the epithelial-to-mesenchymal (EMT) or endothelial-to-mesenchymal transition (EndMT). The process involves the loss of characteristic features of epithelial or endothelial cells and the gain of mesenchymal cell markers. A few studies have reported the subsequent differentiation of transitioned mesenchymal cells to myofibroblasts.
Cell Signaling:
The underlying mechanisms can provide crucial insights into the development and progression of disease. Transforming growth factor β (TGFβ) and hypoxia-inducible factor 1α (HIF-1α)-based signaling pathways have been implicated in fibrosis and carcinoma, respectively. A research study reported that blocking the TGFβ pathway did not affect fibrosis, thus indicating the involvement of other pathways.
Drug Development:
Extensive ongoing research has generated new leads for therapeutic development. Primary kidney fibroblasts serve as an in vitro model for preclinical investigation for the evaluation of the efficacy and toxicity of drugs. Research for exploring their potential as prognostic biomarkers in renal cell carcinoma is also underway.
Heterogeneity:
They also demonstrated phenotypic and functional heterogeneity. Conventional marker or morphology-based identification is challenging. Therefore, several research groups have been conducting sequencing studies on kidney fibroblasts to recognize key features of distinct subpopulations.
Drug Delivery:
Optimization of drug delivery systems eliminates any off-target effects that can lead to systemic toxicity in the long term. Various nanoparticle and hydrogel-based approaches have been targeting fibroblasts, considering their role in kidney disease.
In Vitro Culture Models:
Researchers are experimenting with the kidney fibroblast culture to mimic the in vivo system. Their co-culture with other renal cells has been useful to elucidate the complex intercellular cross-talk, and their culture on scaffolds offers a preliminary three-dimensional (3D) model for better representation of tissue-specific cell signaling.
Conclusion
The rising morbidity and mortality due to CKD require effective therapeutic interventions. The limited efficacy and severe adverse complications of the current medications have prompted further research. Kidney fibroblasts are crucial in the progression of kidney diseases and serve as suitable candidates for drug discovery. They provide a cost-effective and simple method for high-throughput drug screening. Numerous research groups are working on primary kidney fibroblasts to delineate their underlying epigenetic, genetic, and metabolic control in pathological conditions.
Kosheeka provides the primary renal fibroblasts from humans and animals to meet your research requirements. Each lot of kidney fibroblasts is tested for functionality, sterility, and viability. These kidney fibroblasts are amenable to high-throughput drug screening, 3D modeling etc.
FAQs
Q: What is the main function of kidney fibroblasts?
Renal fibroblasts produce the extracellular matrix (ECM) of the kidneys, supporting their structure.
Q: How do fibroblasts contribute to CKD?
Fibroblasts stimulate the healing mechanisms to repair tissue injury. The repetitive or severe injury deregulates the healing process, causing excessive accumulation of ECM that impedes the structure and function of the kidneys.
Q: What are myofibroblasts?
Myofibroblasts have properties of smooth muscle cells, thereby showing contractility. This property is helpful to contract the wound and reduce its size.
Q: What is epithelial-to-mesenchymal transition (EMT)?
The transition involves the gradual loss of epithelial characteristics and acquisition of mesenchymal characteristics. This process has been implicated in the myofibroblast formation.
