Angiotensin II- and Salt-Induced Kidney Injury

Questions: 1. What are the novel findings the manuscript Angiotensin II- and Salt-Induced Kidney Injury? 2. What is the effect of low and high salt on blood pressure and kidney function in normal mice (C57)? 3. What is the mechanism of actions of hydralazine and eplerenone? 4. Why there is an increase level of plasma aldosterone in THM mouse model? 5. What are the mechanisms involved in Ang II/salt-induced nephropathy? 6. What did you find most difficult or interesting regarding the assignments? Answers: 1. The novel findings in Angiotensin II- and Salt-Induced Kidney Injury is that activation of Rac-1/ MR cascade is responsible for the renal dysfunction. The Rac-1 and MR cascade activated by the increasing the concentration of plasma aldosterone and to inhibit renal injury, a selective mineralocorticoid (MR) inhibitor such as eplerenone or adrenalectomy found to beneficial in deactivating MR signaling. 2. The effect of low and high salt concentration on blood pressure and kidney function in normal mice (C57) is that systolic blood pressure (SBP) and urinary albumin excretion showed no significant changes in C57 as compared to THM-HS mice. This relates that Ang II with high salt concentration is responsible for salt sensitivity of BP and kidney injury, not high salt concentration alone. 3. Eplerenone is a selective mineralocorticoid (MR) inhibitor. The PAI-1, CTGF, Sgk-1 are the effectors of MR signalling in the kidney. MR signalling also activated by increasing salt concentration. The renal dysfunction and MR activation is dependent on plasma aldosterone status. It inhibit MR activation and hence reduced albuminuria. Hydralazine helps to lower systolic blood pressure but does not improve condition related to salt induced albuminuria, podocyte injury or renal abnormalities. 4. The plasma aldosterone levels were increased in THM-LS mice as compared to C-57, because high concentration of salt reduces plasma aldosterone concentration but activated renal RAC-1 MR cascade and thus caused renal dysfunction. 5. Adrenalectomy suppressed the activation of both Rac-1 and MR signalling cascade. Therefore, aldosterone/MR system is involved in the Ang II/salt-induced nephropathy. The effect of adrenalectomy and aldosterone supplementation was examined in TMS-HS. The adrenalectomy reduced plasma aldosterone and thus reduced BP and prevented albuminuria, whereas aldosterone supplementation increases plasma aldosterone and thus BP increases and caused renal dysfunction. 6. The most interesting part is to reveal the action of the Rac-1/ MR cascade, that is, how Rac-1/ MR cascade gets activated and causes renal dysfunction and how renal dysfunction caused by Ang II/ salt. The most difficult part is to understand the mechanism of Mineralocorticoid cascade in the renal dysfunction and to interpret the data in finding out the causative agent of renal dysfunction. References: 1. Kawarazaki W. (2012). Angiotensin II- and Salt-Induced Kidney Injury through Rac1-Mediated Mineralocorticoid Receptor Activation. J Am Soc Nephrol. 23, pp. 9971007.2. Nagase M. (2010). Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome. Clin Exp Nephrol. 14, pp. 303314.3. Shibata S., Nagase M., Yoshida S., Kawarazaki W. (2008). Modification of mineralocorticoid receptor function by Rac1 GTPase: Implication in proteinuric kidney disease. Nat Med. 14, pp. 13701376.4. Lea W. (2009). Aldosterone antagonism or synthase inhibition reduces endorgan damage induced by treatment with angiotensin and high salt. Kidney Int. 75, pp. 936944.