LAUSR

Hypertension is the second leading cause of chronic kidney disease in the world. Angiotensin II (Ang II) induced Toll-like receptor 4, TLR4, activation contributes to hypertension-induced renal inflammation and fibrosis. Recently, we showed that mice with dysfunctional TLR4 are protected from renal injury by reducing inflammation and oxidative stress. Autophagy is a protective mechanism that degrades protein aggregates and damaged organelles to maintain intracellular homeostasis and cell integrity. Consequently, defective autophagy in the kidney can lead to cellular injury. A growing body of evidence implicates altered autophagy to various kidney diseases including hypertension. TLRs are known to play a significant role in autophagy, however, the role of TLR4 mediated autophagy in hypertension induced renal injury remains unclear. We hypothesized that TLR4 deficiency reduces Ang II induced renal injury by suppressing autophagy in hypertensive kidney. C3H/Heouj mice with normal TLR4 and C3H/Hej LPS-d with mutant TLR4 (TLR4 deficiency) aged 10-12 weeks were treated without or with Ang II (1000 ng/kg/d) for 4 weeks. In response to Ang II, TLR4 deficient mice showed increased glomerular filtration rate (GFR) (892.43 ± 56.72 vs. 712.63 ± 46.82 μL/min./100g b.w.) and increased renal vascular density and reduced renal cortical resistive index compared to mice with normal TLR4. Ang II treated mice with normal TLR 4 showed increased reactive oxygen species (ROS) generation and upregulation of IκB and NF-kβ compared to TLR4 deficient mice. Ang II increased the expression of autophagy marker proteins, LC3 I/II, p62, Atg5, Beclin1 in the kidney of mice with normal TLR4 compared to mice with TLR4 deficiency. Our data suggests that Ang II induced TLR4 activation upregulates autophagy whereas in C3H/Hej LPS-d mice with TLR4 deficiency, autophagy is unaffected and protects the kidney from hypertension injury.