Janus-Faced: Molecular Mechanisms and Versatile Nature of Renal Fibrosis

Renal fibrosis is a major hallmark of CKD, regardless of the underlying etiology. In fibrosis development and progression, myofibroblasts play a pivotal role, producing extracellular matrix and interacting with various resident cells in the kidney. Over the past decade, the origin of myofibroblasts has been thoroughly investigated. Emerging evidence suggests that renal myofibroblasts originate from several cellular sources, including resident fibroblasts, pericytes, and bone marrow–derived cells. The contribution of resident fibroblasts is most crucial, and currently available data strongly suggest the importance of functional heterogeneity and plasticity of fibroblasts in kidney disease progression. Resident fibroblasts acquire distinct phenotypes based on their local microenvironment and exert multifactorial functions. For example, age-dependent alterations of renal fibroblasts make a significant contribution to the formation of tertiary lymphoid tissues, which promote local inflammation after injury in the aged kidney. In conjunction with fibrosis development, dysfunction of resident fibroblasts provokes unique pathologic conditions including renal anemia and peritubular capillary loss, both of which are major complications of CKD. Although renal fibrosis is considered detrimental in general, recent studies suggest it has beneficial roles, such as maintaining functional crosstalk with injured proximal tubular cells and supporting their regeneration. These findings provide novel insight into the mechanisms of renal fibrosis, which could be regarded as an adaptive process of kidney injury and repair. Precise understanding of the functional heterogeneity of resident fibroblasts and myofibroblasts has the potential to facilitate the development of novel therapeutics against kidney diseases. In this review, we describe the current perspective on the origin of myofibroblasts and fibroblast heterogeneity, with special emphasis on the dual aspects of renal fibrosis, both beneficial and detrimental, in CKD progression.