Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin

Abstract

Background/Aims: Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis. Methods: We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT₁R) blocker telmisartan (2 mg · kg^–1 · day^–1) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function. Results: Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine²⁴⁴⁸ phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats. Conclusions: Our observations suggest that Ang II activation of the AT₁R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.

Overnutrition, mTOR signaling, and cardiovascular diseases

“…Further, hypertensive rats overexpressing the renin gene display increased renal tissue Ser 2448 phosphorylation of mTOR and downstream S6K1 in concert with tubulointerstitial fibrosis. Blockade of the AT 1 R reduces mTOR/S6K activation and attenuates the tubulointerstitial structural abnormalities and proteinuria observed in the kidneys of these rats (86).…”

“…An impact of MR signaling related to its activation of the mTOR/ S6K pathway is highlighted by the finding that MR antagonism targets mTOR/S6K1 signaling to reduce fibrosis, enhance proximal tubule integrity, and lessen proteinuria (88). In this context, the amelioration of renal fibrosis following mTOR inhibition with rapamycin has been shown to be related to reductions in phosphorylation/activation of S6K1 (86). Further, hypertensive rats overexpressing the renin gene display increased renal tissue Ser 2448 phosphorylation of mTOR and downstream S6K1 in concert with tubulointerstitial fibrosis.…”

“…Enhanced activation of mTOR/S6K is associated with cardiac hypertrophy and impaired endothelial function, and rapamycin treatment to reduce this activation corrects some of these abnormalities (30). Treatment with rapamycin has also been shown to prevent renal fibrosis and proteinuria in a rodent model of obesity and diabetic nephropathy (86). In this review, we will highlight how excess activation of the mTOR/S6K promotes metabolic and cardiovascular abnormalities and discuss potential therapeutic strategies to mitigate these abnormalities.…”

Over-nutrition contributes to tubulointerstitial fibrosis by targeting nutrient-sensing kinases

“…Indeed, mice deficient for S6K (S6K -/-) fed a high fat diet are protected against obesity and insulin resistance, and have improved survival. 8 Recent in vitro and ex vivo studies of cardiac and vascular tissue suggest that angiotensin (Ang) II phosphorylation of S6K promotes cardiac fibrosis.…”

“…8,10 In this context, recent work further suggests that AngII directly targets proximal tubule-specific N-cadherin through mTOR/S6K1 in 7 To conclude, over-nutrition activation of mTOR/S6K is likely dependent on the RAS in TIF, including loss of adherens junction proteins. Future work should clarify how mTO'R/S6K regulates the actin cytoskeleton/adherens junction for TIF to occur and the effects of fructose on mTOR/S6K.…”