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

Abstract Chronic kidney disease (CKD) and ageing inhibit tissue regeneration and increase risks of organ fibrosis and cardiovascular disease. Increased numbers of leukocytes are present in the circulation and within the kidney of ageing individuals and patients with CKD where they correlate with progressive fibrosis. The involvement of activated leukocytes in progressive renal and systemic fibrosis remains incompletely understood. Here we show that renal leukocyte derived tumour necrosis factor alpha (TNFα) promotes renal and cardiac fibrosis via downstream induction of Indian Hedgehog (IHH). We identify the Ubiquitin D expressing ‘inflammatory’ proximal tubular epithelia (iPT) population responsible for TNFα/NFκB induced IHH production. iPT cells are upregulated in the kidney in experimental murine and human renal disease and ageing. iPT derived IHH activates canonical Hedgehog signalling in Gli1+ stromal cells, inducing their activation, proliferation and fibrosis in the surrounding kidney and in remote organs including the heart. This can be inhibited by selective genetic Ihh deletion from Pax8 expressing renal epithelia, or pharmacological blockade of TNFα, NFκB or Hedgehog signalling. This data connects inflammation to progressive renal and cardiac fibrosis and identifies new targets for anti-fibrotic therapies.

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Etanercept Ameliorates Cardiac Fibrosis in Rats with Diet-Induced Obesity

Pharmaceuticals ◽

10.3390/ph14040320 ◽

2021 ◽

Vol 14 (4) ◽

pp. 320

Author(s):

Chia-Chen Hsu ◽

Yingxiao Li ◽

Chao-Tien Hsu ◽

Juei-Tang Cheng ◽

Mang Hung Lin ◽

...

Keyword(s):

High Fat Diet ◽

Cardiac Fibrosis ◽

Cardiac Injury ◽

Vehicle Group ◽

Necrosis Factor Alpha ◽

Etanercept Treatment ◽

Diet Induced Obesity ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

Diet-induced obesity (DIO) is considered the main risk factor for cardiovascular diseases. Increases in the plasma levels of tumor necrosis factor alpha (TNF-α) is associated with DIO. Etanercept, a TNF-α inhibitor, has been shown to alleviate cardiac hypertrophy. To investigate the effect of etanercept on cardiac fibrosis in DIO model, rats on high fat diet (HFD) were subdivided into two groups: the etanercept group and vehicle group. Cardiac injury was identified by classic methods, while fibrosis was characterized by histological analysis of the hearts. Etanercept treatment at 0.8 mg/kg/week twice weekly by subcutaneous injection effectively alleviates the cardiac fibrosis in HFD-fed rats. STAT3 activation seems to be induced in parallel with fibrosis-related gene expression in the hearts of HFD-fed rats. Decreased STAT3 activation plays a role in the etanercept-treated animals. Moreover, fibrosis-related genes are activated by palmitate in parallel with STAT3 activation in H9c2 cells. Etanercept may inhibit the effects of palmitate, but it is less effective than a direct inhibitor of STAT3. Direct inhibition of STAT3 activation by etanercept seems unlikely. Etanercept has the ability to ameliorate cardiac fibrosis through reduction of STAT3 activation after the inhibition of TNF-α and/or its receptor.

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Effect of TGF-beta 1 and TNF-alpha on the plasminogen system of rat proximal tubular epithelial cells.

Journal of the American Society of Nephrology ◽

10.1681/asn.v82184 ◽

1997 ◽

Vol 8 (2) ◽

pp. 184-192 ◽

Cited By ~ 1

Author(s):

J J Kanalas ◽

U Hopfer

Keyword(s):

Epithelial Cells ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tubular Epithelial Cells ◽

Plasminogen Activator Inhibitor 1 ◽

Necrosis Factor Alpha ◽

Heymann Nephritis ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Factor Alpha

Rat proximal tubular epithelial cells derived from Wistar-Kyoto and spontaneously hypertensive rats were grown to confluency on semipermeable tissue culture inserts, and the plasminogen system of these cells was analyzed using enzyme assays, Western analysis, zymography, and reverse transcriptase-polymerase chain reaction. The tubular epithelial cells are capable of activating exogenous plasminogen to plasmin by endogenous plasminogen activators. The cells produce tissue-plasminogen activator, urokinase-plasminogen activator, plasminogen activator inhibitor-1, and urokinase-plasminogen activator receptor. These cells also produce the Heymann nephritis autoantigen, gp330 (megalin), and an associated protein of 45 kd (RAP). Incubation with transforming growth factor-beta 1 resulted in a decrease in plasminogen activation, primarily because of an increase in plasminogen activator inhibitor-1 RNA and protein and a decrease in u-PA RNA as noted by quantitative reverse transcriptase-polymerase chain reaction, Western analysis, and zymography. Incubation of these cells with tumor necrosis factor-alpha resulted in an increase in plasminogen activating ability, presumably through an increase in urokinase. Gp330 and the associated 45-kd protein (RAP) RNA were decreased in cells treated with tumor necrosis factor-alpha. The data presented indicates that these transformed proximal tubular epithelial cells may be used to study changes that may occur during Heymann nephritis with respect to the plasminogen system and the autoantigen gp330.

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