Autophagy contributes to the development of salt‐induced hypertension and kidney injury in Dahl S rats

Abstract

Studies were carried to determine the role of autophagy in the development of renal injury in the hypertensive Dahl salt‐sensitive (SS) rat fed a high‐salt (HS; 4.0% NaCl) diet. Autophagy is an essential process (autophagosome formation, maturation, fusion with lysosome, release of macromolecular back into cytosol) required to remove misfolded proteins and damaged organelles (mitochondria, endoplasmic reticulum and peroxisomes) from all cells. It is a dynamic process (“autophagic flux”) and challenged in cells faced with excessive metabolic workloads such as the renal nephrons in kidneys of SS rats fed a HS diet. The tubular mitochondria of SS rats fed a HS produce excess reactive oxygen species (ROS) which we have found can activate mammalian target of rapamycin complex 1 (mTORC1). We have reported that the elevation of renal tissue H2O2 in kidneys of SS rats fed a HS diet can activate mTORC1 and that inhibition of this pathway with rapamycin attenuated salt‐induced hypertension and kidney injury. It is also known that mTORC1 plays a crucial role in regulating autophagy but the extent to which these events contribute to the renal injury observed in the SS rat has not been examined.GoalStudies were carried out in male SS rats to determine the effects of a HS diet (4.0% NaCl) upon the “autophagic flux” of the kidneys. SS rats (n=6 each group) were studied at days 3 or 21 of the HS diet and compared to those receiving a 0.4% NaCl diet. Rat received either the HS diet treated with vehicle, or HS plus daily rapamycin (IP, 1.5 mg/kg per day); Western blot analysis of renal cortical and medullary tissue LCII (microtubule‐associated protein light chain 2) and BECLIN1 protein levels was carried out as an index of autophagic flux.ResultsWhile no changes in the LCII levels were observed at day 3 of HS, a significant reduction was found in both the cortex and medulla after 21 days of HS compared to rats fed 0.4% NaCl. In rapamycin treated SS rats, both the renal cortex and medulla showed significantly greater increases of LCII and BECLIN1 compared with vehicle treated rats suggested an increase of autophagic index. Together, our observations suggest that the attenuation of salt‐induced hypertension and kidney injury in rapamycin treated SS rats may be in part the consequence of increased autophagic influx.Support or Funding InformationHL‐116264