Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats

Abstract

BackgroundThe platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.AimsIn this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN.Materials and MethodsNeutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily.ResultsAt Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.ConclusionsThe early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation.

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

“…6 days) damages kidneys, especially renal proximal tubular cells. Similar histopathological damage was also shown in previous rodent studies (Arlt et al 2011b; Baudoux et al 2012; Debelle et al 2002, 2003; Pozdzik et al 2016). Apart from proximal tubular necrosis, both atrophy and fibrosis with a lymphocytic infiltrate were present (Baudoux et al 2012).…”

“…treatment with 5 mg/kg bw AA over 8 days (Baudoux et al 2012) or oral treatment with 5 mg/kg bw AAI over 21 days (Arlt et al 2011b) led to necrosis in proximal tubules in mice. Renal necrosis was also observed in another rodent model, in which rats were treated with subcutaneous injections of either 10 mg/kg bw AA for 10 days (Debelle et al 2002) or 15 mg/kg bw AA for 5 days (Pozdzik et al 2016). In the present study, experimental AAN was studied in mice as previously described (Baudoux et al 2012), but Trp53 (+/+), Trp53 (+/−) and Trp53 (−/−) mice were treated with a daily i.p.…”

Renal disease pathophysiology and treatment: contributions from the rat

“…In a rat model of aristolochic-acid-induced nephropathy, the neutralization of TGFβ with anti-TGFβ antibody improved renal function and reduced acute tubular necrosis, interstitial inflammation, vascular rarefaction and myofibroblast accumulation (Pozdzik et al, 2016). The disruption of proximal tubule organelle ultrastructure was also prevented.…”

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches

“…Similarly, another study reported that inhibition of TGF-β by neutralizing anti-TGF-β antibody (1D11) ameliorated the impairment of renal function in AA-induced acute kidney injury in rats [79].…”

“…Similarly, Li and colleagues observed a significant increase in TGF-β 1 expression associated with interstitial fibrosis in mice treated with AA for 30 days [78]. In addition, it was demonstrated that a blockade of the TGF-β signaling pathway ameliorated the impairment of renal function and partially prevented the epithelial-endothelial axis activation and reduction of pericytes-derived PDGFRβ + perivascular cells accumulation in a rat model of AA-induced acute kidney injury [79]. In their study, Pozdzik and colleagues observed, in mice treated with AA at day 35, the accumulation vimentin, α-smooth muscle actin-positive cells, and overexpression of TGF-β [13].…”