Hypoxia and fibrosis in chronic kidney disease: crossing at pericytes.
Chronic kidney disease (CKD) is placing an increasing burden on patients and societies because no decisive therapy has been established. Tubulointerstitial lesions accompanied by fibrosis, inflammatory cells, and capillary rarefaction not only characterize, but also aggravate renal dysfunction in CKD. In this setting, renal cells, particularly tubular cells, suffer from hypoxia caused by the imbalance of blood perfusion and oxygen demand despite their adaptive responses represented by upregulation of hypoxia-inducible factors (HIFs). Fibrosis is a pathological state characterized by excess extracellular matrix (ECM) deposition, which is also a hallmark and causative factor of many chronic diseases including CKD. Recent studies have suggested that the dominant origin of ECM-producing myofibroblasts (MFs) may be pericytes, which are indispensable cells for maintaining proper capillary functions, as they wrap capillaries and stabilize them through a fine-tuned interplay with endothelial cells. During fibrosis, pericytes are activated and detach from capillaries before conversion into MFs, which compromises capillaries and worsens hypoxia. We also discuss how hypoxia and HIFs affect fibrogenesis. Given that hypoxia is caused by insufficient angiogenesis and that fibrosis results from pericyte loss, restoration of pericytes should be an intriguing target for overcoming both hypoxia and fibrosis. We propose the deactivation of MFs to recover lost pericytes as a promising therapy for CKD.
Division of Nephrology and Endocrinology, The University of Tokyo , Bunkyo-ku, Tokyo, Japan.
Takahisa
T
Kawakami
Division of Nephrology and Endocrinology, The University of Tokyo , Bunkyo-ku, Tokyo, Japan.
Imari
I
Mimura
Division of Nephrology and Endocrinology, The University of Tokyo , Bunkyo-ku, Tokyo, Japan.
Kumi
K
Shoji
Division of Nephrology and Endocrinology, The University of Tokyo , Bunkyo-ku, Tokyo, Japan.
Tetsuhiro
T
Tanaka
Division of Nephrology and Endocrinology, The University of Tokyo , Bunkyo-ku, Tokyo, Japan.
Masaomi
M
Nangaku
angiogenesis; chronic kidney disease; fibrosis; hypoxia; pericytes