Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus.

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.

Renal inflammation is modulated by potassium in chronic kidney disease: possible role of Smad7.

High-potassium diets have been shown to be beneficial in cardiovascular disease partly because of a blood pressure-lowering effect. The effect of potassium on inflammation has not been studied. We investigated the influence of potassium supplementation on the degree of renal inflammation and the intracellular signaling mechanisms that could mediate inflammation in chronic kidney disease (CKD). CKD was created in male Sprague-Dawley rats by subtotal nephrectomy. Two groups of CKD rats were pair fed with diets containing 2.1% potassium (potassium-supplemented diet) or 0.4% potassium (basal diet). Body weight, blood pressure, and blood and urine electrolytes were measured biweekly. The animals were euthanized at week 8, and the remnant kidneys were analyzed by histology, immunohistochemistry, Western blotting, and real-time quantitative PCR. In the CKD pair-fed groups, blood potassium concentration did not differ significantly, but blood pressure was lower in the potassium-supplemented group. Compared with the basal diet, potassium supplementation decreased renal tubulointerstitial injury and suppressed renal inflammation as evidenced by decreased macrophage infiltration, lower expression of inflammatory cytokines, and decreased NF-kappaB activation. These renoprotective effects were associated with downregulation of renal transforming growth facto-beta, upregulation of renal Smad7, and lower blood pressure. Our results show that potassium supplementation can reduce renal inflammation and hence, could modulate the progression of kidney injury in CKD.