CROSSTALK BETWEEN RAS COMPONENTS IN KIDNEY DISEASES

Kidney diseases are life-threatening degenerative conditions with higher rates of mortality and morbidity worldwide. Depending on several factors, after an initial subclinical stage, these diseases can progress from an initial subclinical stage to different dysfunctional stages, known as acute kidney injury (AKI) or chronic kidney disease (CKD), which can evolve to complete organ failure. Regardless of the etiology, the development of tubule-interstitial injury and proteinuria, associated with dysfunction of tubular protein reabsorption, are common factors in the pathogenesis of many kidney diseases. However, the molecular mechanisms underlying these processes are still poorly understood. One possibility is the involvement of the components of Renin-Angiotensin System (RAS). There has been an observed increase in angiotensin II (Ang II), an octapeptide from the classical RAS, and a reduction in angiotensin-(1-7) [Ang-(1-7)], a heptapeptide from the alternative RAS, in kidney tissues in different kidney diseases. The use of angiotensin receptor blockers (ARBs), inhibitors of the classical RAS, has been extensively employed due to their anti-proteinuric actions and their ability to improve outcomes for patients with CKD. However, it remains unclear how the interaction between these peptide pathways occurs in the early stages of kidney diseases. Herein, we discuss how Ang II and Ang-(1-7) modulate the dysfunction of tubular protein reabsorption and the development of tubule-interstitial injury in subclinical forms of kidney disease. Our findings show that blocking Ang II effects using ARBs or increasing systemic Ang-(1-7) using both pharmacological means (animals treated with an oral formulation containing Ang-(1-7) included in hydroxypropyl-β-cyclodextrin) and genetic tools (L-3292 transgenic rat strain), leads to the amelioration of tubular proteinuria and the development of tubular injury in animal models of subclinical AKI and CKD. These results suggest that the imbalance between the classical and alternative arms of RAS could be the mediating mechanism involved in the development of tubule-interstitial injury in the early stages of kidney diseases. These findings expand our current knowledge regarding the involvement of RAS components in the development of tubular injuries, opening new possible therapeutic strategies to prevent or at least halt the progression of different kidney diseases.