Abstract
Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in Col4a3-/- mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 (Fstl1) was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the Fstl1 receptors, Tlr4 and Dip2a, increased in both Col4a-/- mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope® (Advanced Cell Diagnostics, Newark CA, USA) localized Fstl1 to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed Fstl1 confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. FSTL1 expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline FSTL1 mRNA levels. FSTL1 is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD.
Highlights
The prevalence and progression of chronic kidney disease (CKD) remains a global clinical challenge, and the development of end stage kidney disease is a costly outcome requiring therapies like dialysis and kidney transplantation
Blockade of the renin angiotensin system remains the first line approach to limiting progression of CKD and reducing end stage kidney disease (ESKD), especially in the setting of proteinuria, while new data suggest that the use of sodium glucose co-transport-2 (SGLT2) inhibitors may affect progression broadly, and this is an active area of ongoing investigation [4]
We utilized Col4a3-/- mice because they develop early proteinuria followed by TI inflammation and fibrosis leading to mortality by 9–10 weeks of age [5,7]
Summary
The prevalence and progression of chronic kidney disease (CKD) remains a global clinical challenge, and the development of end stage kidney disease is a costly outcome requiring therapies like dialysis and kidney transplantation. This underscores the important need to develop new and effective treatments to lessen the burden of CKD, but we require a better understanding of the pathogenesis of CKD progression in order to identify new targets for therapy [1]. The decline in glomerular filtration in CKD, including diseases that affect the kidney glomerulus, is associated with pathology in the kidney tubulointerstitium.
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