Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis

Abstract

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1 + ) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 + cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 + cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell–resolution transcriptomic analysis, we identified an “inflammatory” proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)–induced IHH production in vivo. TNF-induced Ubiquitin D ( Ubd ) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1 + cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8 -expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1 + cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

Artesunate Alleviates Kidney Fibrosis in Type 1 Diabetes with Periodontitis Rats via Promoting Autophagy and Suppression of Inflammation

“…AMPK is an important energy sensor, which can regulate the body’s energy metabolism, induce apoptosis, improve inflammation, regulate oxidative stress, and promote autophagy. , Therefore, inhibition of AMPK can aggravate the occurrence and development of renal fibrosis, and AMPK activation can inhibit renal fibrosis. − The inflammatory response involved in inflammatory cytokines/cells promotes the process from repair response to injury in the kidney, and the persistent inflammatory response accelerates the process of renal fibrosis. ,,, TNF-α can affect the morphology and skeleton of mesangial cells and stimulate the proliferation of mesangial cells and the proliferation of fibroblasts, which are the main protein source of ECM. , IL-1β induces an inflammatory response and stimulates the synthesis and secretion of TNF-α, which synergistically promotes the development of renal fibrosis. NF-κB is a regulatory factor of inflammation and immune response, closely related to DN’s occurrence and development. , Under high glucose conditions, NF-κB accumulates in the cytoplasm, leading to a large amount of inflammation in the kidney tissue and causing glomerular and renal interstitial fibrosis. The NF-κB signaling pathway can participate in the pathophysiology and renal interstitial fibrosis of early DN through a variety of mechanisms. , In addition, activated AMPK can also block the NF-κB signaling pathway, improve the blood glucose level of diabetic rats, reduce the expression of pro-inflammatory factors, and play an anti-inflammatory role. , Therefore, we hypothesized that AMPK may aggravate kidney injury in type 1 diabetic rats with periodontal disease by regulating the TGF-β and NF-κB signaling pathways.…”

“…NF-κB is a regulatory factor of inflammation and immune response, closely related to DN’s occurrence and development. 55 , 56 Under high glucose conditions, NF-κB accumulates in the cytoplasm, leading to a large amount of inflammation in the kidney tissue and causing glomerular and renal interstitial fibrosis. The NF-κB signaling pathway can participate in the pathophysiology and renal interstitial fibrosis of early DN through a variety of mechanisms.…”

Mincle receptor in macrophage and neutrophil contributes to the unresolved inflammation during the transition from acute kidney injury to chronic kidney disease

“…found that the KLF4 deficiency in myeloid cells augmented TNF-α production, thereby exacerbating necroptosis of TECs and renal interstitial fibrosis in two murine models of CKD induced by nephrotoxic serum nephritis and unilateral ureteral obstruction, however, this effect was mitigated by macrophage-specific TNF deletion ( 36 ). Utilizing single-cell transcriptomics, TNF from activated leukocytes drove Gli1 + cell proliferation and fostered renal fibrosis by elevating Indian Hedgehog (IHH) release from TECs ( 37 ). Moreover, an unbiased transcriptomic approach revealed shared molecular signatures of an activated kidney TNF pathway and unfavorable clinical outcomes among patients diagnosed with either minimal change disease or focal segmental glomerulosclerosis, highlighting TNF as a pivotal driver in the progression of these diseases ( 38 ).…”

The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance

“…Hallmarks of aging are functionally intertwined and drive the pathophysiology of many chronic disorders, affecting tissues directly involved in IR development ( 35 , 36 ). Very recently, Ubd expression was observed in human proximal tubular cells in vitro and during aging ( 37 ). A novel role of Ubd in immune metabolic regulation that impact aging and chronic disease has been revealed, Ubd KO extended lifespan and enhanced insulin sensitivity in skeletal muscle tissues ( 38 ).…”