What can target kidney fibrosis?

Abstract

Fibrosis, a characteristic of all chronic kidney diseases, is now recognized to be an independent predictor of disease progression. Deposition of pathological matrix in the walls of glomerular capillaries, the interstitial space and around arterioles both predicts and contributes to functional demise of the nephron and its surrounding vasculature. Recent identification of the major cell populations of fibroblast precursors in the kidney interstitium as pericytes and tissue-resident mesenchymal stem cells, and in the glomerulus as podocytes, parietal epithelial and mesangial cells, has enabled the study of the fibrogenic process in much greater depth directly in the fibroblast precursors. These cells are not only matrix-producing cells, but are also important innate immune surveillance cells that regulate the inflammatory process, exacerbate tissue damage by release of radicals and cytokines, and contribute to parenchymal and microvascular dysfunction by aberrant wound-healing responses. Innate immune signaling in fibroblasts and their precursors is intimately intertwined with the process of fibrogenesis. In addition, genomic and genetic studies also point to defective responses in loci close to genes involved in solute transport, metabolism, autophagy, protein handling and vascular homeostasis, principally in the epithelium and endothelium, as upstream drivers of the fibrotic process, indicating that cellular crosstalk is vital for development of fibrosis. As we move beyond TGFβ inhibition as a central target for fibrosis, targeting innate immune signaling and metabolic dysfunction appear increasingly tenable alternative targets for novel therapies.

MiR‐9‐5p protects from kidney fibrosis by metabolic reprogramming

“…10 Upregulation of genes related to mitochondrial function and to the PPARα signaling pathway was observed by anti-miR-21 treatment. 67-69 A significant degree of the pro-fibrotic actions attributed to miR-21 in the kidney are related to profound and specific metabolic derangements closely associated with mitochondrial dysfunction.…”

“…1,2 Recent studies have demonstrated a global defect in fatty acid oxidation (FAO) leading to a compromise in the main source of energy for tubular epithelial cells. 10 However, they have been scarcely effective [11][12][13][14] and thus there is urgent need to develop new therapeutic strategies. 3 While there has been significant progress in the understanding of renal fibrogenesis, [6][7][8] no effective therapy is available to prevent its progression or revert tissue damage.…”

Epithelial innate immunity mediates tubular cell senescence after kidney injury

“…Recently, multiple studies identified multipotent mesenchymal stromal progenitor cells (pericytes) as the cell population that is responsible for collagen deposition after injury, in response to Hedgehog-mediated (Hh-mediated) proproliferative and profibrogenic signaling from the epithelium (5,6). Kidney fibrosis has also been correlated with arrest of tubular epithelial cells (TECs) in the G2/M phase of the cell cycle (7)(8)(9), which suggests that the epithelium plays a primary role in the progression of kidney disease. However, the factors that contribute to the cell cycle arrest are not known.…”

IL-11 is a crucial determinant of cardiovascular fibrosis

“…In the heart, fibrosis causes mechanical and electrical dysfunction 1,2 and in the kidney, it predicts the onset of renal failure 3 . Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor 4,5 , but its inhibition is associated with side effects due to its pleiotropic roles 6,7 .…”