Renal Proximal Tubule Injury:Role of Angiotensin II Type 1 Receptor (AT1R) Blockage through Heat Shock Protein 70 (Hsp70)

Abstract

The renal tubules and tubulointerstitial space make up a significant portion of the kidney and are the major sites in response to injuries. The severity of tubular interstitial damage is highly correlated to the degree of decline of renal function, even better than the glomerular lesions do. Increasing evidence shows that proximal tubular epithelial cells (PTECs) play diverse roles in renal repair or progression to chronic kidney disease (CKD). The innate immune characteristics of PTECs enable them to act as immune responders to a wide range of insults, with the consequent production and release of bioactive mediators that drive interstitial inflammation and fibrosis. The renin angiotensin system is a critical promoter of fibrogenesis. It represents a nexus among glomerular capillary hypertension, barrier dysfunction and renal tubular injury caused by abnormally filtered proteins. Transforming growth factor (TGF-) and reactive oxygen species (ROS) are the key mediators of the pro-fibrotic effect of angiotensin II causing apoptosis and epithelial-to-mesenchymal transition of the renal tubular epithelium. Angiotensin II via angiotensin type 1 receptor (AT1R) regulates the activation and trans-differentiation of pericytes and fibrocytes into scar-forming myofibroblasts. Detachment and phenotypic changes of the former, can lead to the loss of peritubular capillaries and also contribute to hypoxia-dependent fibrosis. Many effects of angiotensin II are dependent on the AT1R stimulation of reactive oxygen species (ROS) production by NADPH oxidase. Angiotensin II upregulation stimulates oxidative stress in proximal tubules. The NADPH oxidase 4 (Nox4) is abundantly expressed in kidney proximal tubule cells. Induction of the stress response includes synthesis of heat shock protein 70, a molecular chaperone that has a critical role in the recovery of cells from stress and in renoprotection, guarding cells from subsequent insults. Hsp70 chaperone functions in part by driving the molecular triage decision, which determines whether proteins enter the productive folding pathway or result in client substrate ubiquitination and proteasomal degradation. This review discusses the current mechanisms of tubulointerstitial fibrosis progression and the increasingly important role of the proximal tubule injury in driving inflammation and fibrosis. The renoprotective role of the AT1R blockage through Hsp70, as a possible molecular target for therapeutic strategy against renal PTECs injury, is discussed.