Angiotensin II and Its Role in Tubular Epithelial to Mesenchymal Transition Associated with Chronic Kidney Disease

Abstract

Activation of the intra-renal renin-angiotensin system (RAS) and the subsequent generation of angiotensin II (Ang II) are important mediators of haemodynamic changes in both health and disease. However, the effects of locally produced Ang II are not limited to haemodynamic actions. Ang II is also an important stimulus for tubular hypertrophy with the induction of growth factors, including transforming growth factor (TGF)-β₁ and connective tissue growth factor. In this article, we explore the direct pro-fibrotic effects of Ang II and its role in inducing tubular epithelial to mesenchymal transition (EMT, also known as type 2 EMT), a known mediator of renal fibrogenesis. There is accumulating evidence that Ang II is able to induce EMT by both TGF-dependent and TGF-independent actions, both in vitro and in vivo. Moreover, blockade of the RAS has synergistic renoprotective effects across a number of causally different forms of renal disease. There is hope that targeted combinations to offset angiotensin-converting enzyme escape in the setting of RAS blockade will eventually achieve the long-term efficacy that has been expected for so long.

Genipin ameliorates hypertension-induced renal damage via the angiotensin II-TLR/MyD88/MAPK pathway

“…In the current study with HMCs, we found that genipin significantly reduced Ang II-induced cell proliferation. Moreover, Ang II is able to promote ROS production and inflmmatory responses, which eventually leads to apoptosis and necrosis of renal tubular epithelial cells [32].…”

Cardiorenal Syndrome Type 1

“…Angiotensin II is also known to be a potent stimulator of the sympathetic nervous system, which increases systemic vascular resistance, venous tone, and congestion. Angiotensin II has direct trophic effects on cardiomyocytes and renal tubular cells that promotes cellular hypertrophy, apoptosis, and fibrosis (56). Angiotensin II accounts for approximately 50% of the stimulation of aldosterone release from the adrenal gland, which increases renal sodium reabsorption and causes sodium retention.…”

Inhibition of cellular transdifferentiation by losartan minimizes but does not reverse type 2 diabetes-induced renal fibrosis

“…21,22 In the present study, we observed the involvement of EMT and MFT in the mechanism underlying fibrogenesis using a model of type 2 diabetes. The blockade of the AT1 receptor was able to improve the renal function, but could not induce regression of the pre-existing EMT, MFT and renal fibrosis.…”

“…41 AngII is able to activate Smad signaling via a TGF-β1-independent process, 42,43 Smad proteins participate in AngII-induced EMT. [42][43][44][45] In addition, AngII stimulates the expression of connective tissue growth factor (CTGF) through a TGF-β1-independent pathway, 22,42 and CTGF was shown to be an integral component of Ang-II-induced EMT, as blockade of CTGF attenuated this process. 46 In summary, stabilization of cell transition and fibrogenesis was clearly observed in the losartan-treated group, which presented levels of all markers similar to the pretreatment values (D12 group), with the exception of proteinuria levels, which reached control values.…”