Aliskiren

Aliskiren (trade names Tekturna, U.S.; Rasilez, U.K. and elsewhere) is the first in a class of drugs called direct renin inhibitors.Aliskiren current licensed indication is essential (primary) hypertension.

The renin inhibitor aliskiren protects rat lungs from the histopathologic effects of fat embolism.[Pubmed:28107310]

J Trauma Acute Care Surg. 2017 Feb;82(2):338-344.

BACKGROUND: Fat embolism (FE) and the consequent FE syndrome occurring after trauma or surgery can lead to serious pulmonary injury, including ARDS and death. Current treatment of FE syndrome is limited to supportive therapy. We have shown in a rat model that the renin angiotensin system plays a significant role in the pathophysiology of FE because drugs interfering with the renin angiotensin system, captopril and losartan reduce the histopathologic pulmonary damage. The purpose of the current study was to determine if inhibition of renin by Aliskiren, an FDA-approved drug for treating hypertension, would produce effective protection in the same model. METHODS: The FE model used intravenous injection of the neutral fat triolein in unanesthetized rats. Intraperitoneal injections of saline or Aliskiren at either 50 or 100 mg/kg were performed 1 hour after FE induction via triolein. Rats were euthanized at 48 hours, and various histologic stains were used to examine the lungs. RESULTS: (1) Fibrosis: rats treated with triolein showed significant fibrotic changes with increased collagen and myofibroblast activation (p < 0.0001 for both trichrome and alpha-smooth muscle actin staining). Aliskiren blocked this inflammatory and profibrotic process to a level indistinguishable from the controls (p < 0.0001 for both trichrome and alpha-smooth muscle actin staining). (2) Fat: rats treated with triolein showed a statistically significant increase in fat (p = 0.0006). Subsequent Aliskiren administration at both doses reduced the size, distribution, and amount of fat droplets (low dose, p = 0.0095; high dose, p = 0.0028). (3) Vessel patency: the low dose of Aliskiren blocked the reduction of lumen patency observed after triolein administration (p = 0.0058). CONCLUSIONS: Aliskiren protected the lungs of rats from gross and histopathologic FE-induced pulmonary damage at 48 hours. Clinical implications include the use of Aliskiren both prophylactically (before certain orthopedic procedures) and therapeutically (after severe trauma) to prevent the consequent severe pulmonary pathologic sequelae.

Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus.[Pubmed:28228402]

Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F914-F925.

The direct renin inhibitor Aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether Aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol.kg dry food(-1).day(-1) for 4 days and 20 mmol.kg dry food(-1).day(-1) for the last 3 days) for 7 days. Some mice were intraperitoneally injected with Aliskiren (50 mg.kg body wt(-1).day(-1) in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, Aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in Aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor Aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.