János Radó’s comment on the 2017 research article of Lin, Zhang, Feng, et al., “Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus”


Purpose of the study

       The purpose of their 2017 study was to investigate whether Aliskiren regulates AQP2 expression in the collecting duct principal cells and whether Aliskiren treatment attenuates lithium-induced nephrogenic diabetes insipidus (NDI).


Physiological background

       In the collecting ducts increased intracellular levels of cAMP activate protein kinase A, which phosphorylates aquaporin 2 (AQP2) with translocation of the water channel from intracellular vesicles to the apical plasma membrane. This results in increased osmotic water permeability and urinary concentration. Angiotensin II stimulates upregulation of renal AQP2 abundance in vivo and in vitro, as well as an increased intracellular trafficking of AQP2 to the plasma membrane. Dysregulation of AQP2 plays a fundamental role in acquired forms of nephrogenic diabetes insipidus, e.g., sustained lithium intake, which are associated with depletion of AQP2 protein from the collecting ducts and a defect in urinary concentration. However, whether the synthesized nonpeptide renin inhibitor Aliskiren regulates AQP2 expression independent of RAS activation is unknown.


The direct renin inhibitor

       The direct renin inhibitor Aliskiren has a high affinity and specificity for human renin and inhibits the enzyme renin by binding to its catalytic site and thus reducing angiotensin II levels in the plasma. In contrast to ACE inhibitors and angiotensin II receptor blockers, Aliskiren decreases plasma renin activity and reduces plasma angiotensin 1 and angiotensin II levels, but strongly increases renin and prorenin concentrations. Increasing evidence shows that Aliskiren has a renal protective effect in animals and in patients with hypertension or diabetes. Interestingly, the antihypertensive and antiproteinuric effects of Aliskiren persist for a long time, even after treatment is discontinued.


Effect of  Aliskiren on the kidney

       Renin may act on the nephrons and collecting ducts via activating the (pro)renin receptor. Nephron and collecting duct-specific deletion of the prorenin receptor is associated with polyuria and impaired countercurrent multiplication, accompanied by reduced levels of medullary aquaporin-2 (AQP2) and Na- K-2CI cotransporter.

       Studies showed that Aliskiren may accumulate in the kidney, where it localizes in glomeruli, afferent arterioles and also in the thick ascending limb of Henle and the medullary collecting ducts, which are important for sodium and water reabsorption as well as urinary concentration, indicating a new mechanism of action for this drug.


Aliskiren treatment

       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-PROTEIN KINASE A pathways.


Effect mechanism of Aliskiren

       Aliskiren decrease the expression of prorenin receptor in rat kidney. Aliskiren treatment was associated with ~20% reduction of prorenin receptor in inner medulla compared with the lithium group, accompanied by increased AQP2 expression and improved polyuria. This suggests that prorenin receptor is unlikely to play a role in lithium-induced urinary concentration defect. The observed improvement of urinary concentration in lithium-induced NDI likely indicates a direct effect of Aliskiren in the collecting ducts, in particular in the principal cells. The direct reininhibitor Aliskiren increased the collecting duct AQP2 expression and partially improved the urine concentration defect in lithium-treated mice, likely by directly activating the cAMP-PROTEIN KINASE A pathway in the principal cells.

       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-PROTEIN KINASE A pathways.


My comments

       Lin et al.’s work shows that Aliskiren is a new drug on the palette which is able to counteract (at least in part) the polyuria induced by lithium treatment. However, from the discovery that a new drug is able to abolish lithium-induced nephrogenic diabetes insipidus to the administration in clinical practice is a long way. According to MEDSCAPE Concomitant use of Aliskiren with other agents acting on the RAAS (e.g., ACEIs or ARBs) is associated with an increased risk of hypotension, hyperkalemia and changes in renal function (including acute renal failure). Furthermore, in the “Interaction checker” there are 19 medicines with which coadministration of Aliskiren is strictly contraindicated, 63 medicines with which coadministration requires closely monitoring. Although Aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus in mice, there are difficulties in the administration of this drug to humans.

       We wrote that in such an important form of psychiatric treatment as lithium is, a serious side effect, the disturbance of water metabolism, can be alleviated by clever use of modern antidiuretic interventions (Radó 2018) combination of excessive doses of desmopressin with indomethacine. It was emphasized by us that it is important to save lithium treatment for millions of people suffering from bipolar disorder and other psychiatric abnormalities in an age when its use has gradually declined and many less-established drugs are preferred. This can be done (at least partly) by demonstrating that treatment of lithium-induced permanent nephrogenic diabetes insipidus is not so hopeless as it appears from some recent articles dealing with lithium induced nephrotoxicity. Our therapeutic armamentarium include several drugs, thiazide diuretics, nonsteroid anti-inflammatory drugs, amiloride and desmopressin. On the basis of the available literature desmopressin alone and in combination with other antidiuretic drugs seemed to be an effective means in counteracting lithium-induced polyuria (Radó 2019a). Whether Aliskiren can belong in this group of antidiuretic medicines remains to be established.

       Zhang and his coworkers found that lithium-induced polyuria is due to resistance of the medullary collecting duct to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE2. Genetic deletion of the P2Y2 receptor offered significant resistance to development of lithium polyuria. This change was accompanied by alterations in PGE2 signaling mediated by a marked decrease in the prostanoid EP3 receptor protein abundance thus attenuating the decrease in cAMP, modulator of arginine vasopressin, in the renal medulla (Zhang, Pop, Carlson and Kishore 2012; Zhang, Hansson, Liu, Kishore 2019).

       Clopidrogel is an antiplatelet drug of the thienopyridine group extensively used in cardiological clinical medicine. Another such drug is prasugral and both are ADP antagonists acting on the P2Y12 receptor. Administration of prasugral as well as clopidrogel completely suppressed lithium-induced polyuria and polydipsia in rats (Zhang, Peti-Peterdi, Brandes et al. 2017)

       Pharmacologic blockade of renal P2Y12 receptor in rodents increases urinary concentrating ability by augmenting the effect of vasopressin on the kidney and ameliorates lithium-induced nephrogenic diabetes insipidus by potentiating the action of vasopressin on the renal collecting duct (Zhang Peti-Peterdi, Müller et al. 2015). This strategy may offer a novel and effective therapy for lithium-induced nephrogenic diabetes insipidus in man.

       Pharmacologic blockade of renal P2Y12 receptor may be combined - at least theoretically - with anti-prostaglandin agents (non-steroidal anti-inflammatory compounds) and supplemented with large doses of desmopressin in the treatment of lithium-induced nephrogenic diabetes insipidus (Radó 2019b). Lithium-induced excessive prostaglandinuria (increased excretion of PGE2) can be prevented by pharmacologic blockade of the renal P2Y12 receptor and antagonized by the administration of indomethacine.

       The present therapy for lithium-induced nephrogenic diabetes insipidus in man is to counter anti-vasopressin action of lithium by administration of thiazide diuretics, antiprostaglandin compounds (indomethacine) combined with large doses of desmopressin. (Amiloride supplements the “present therapy” drug group). The “future” treatment seems to be (on the basis of recent animal experiments) to enhance the sensitivity of the kidney to vasopressin action by administering pharmacologic blockade of renal P2Y12 receptor. (Zhang, Riquier-Brison, Liu, et al. 2018.) On theoretical basis it is conceivable that the present therapy of lithium-induced nephrogenic insipidus perhaps could be combined with the “future” pharmacologic blockade. Whether Aliskiren can belong in this group of antidiuretic medicines remains to be established.

       We are all definitely convinced by the enormous work of Ban (2017), Blackwell (2014), Rybakowski (2017), Severus, Taylor, Sauer et al. (2014) and others that millions suffering from bipolar disorder need lithium treatment and making it safer by eliminating (at least partly) its most frequent side effect lithium polyuria, is a decent goal for both the investigators and physicians.



Ban TA. Neuropsychopharmacology in Historical Perspective. Education in the Field in the Post-Neuropsychopharmacology Era. Prologue. inhn.org.education. September 18, 2017. 

Blackwell B. Lithium Controversy. A historical autopsy. inhn.org.controversies. June 19, 2014. 

Kishore BK, Carlson NG, Ecelbarger CM, Kohan DE, Müller CE, Nelson RD, Peti-Peterdi J, Zhang Y. Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus. Acta Physiol (Oxf), 2015;214(2):176-88. 

Lin Y, Zhang T, Feng P, Qiu M, Liu Q, Li S, Zheng P, Kong Y, Levi M, Li C, Wang W.  Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus. Am J Physiol Renal Physiol, 2017;313:F914-25. 

Radó J. Use of modern antidiuretic agents in the treatment of permanent lithium induced nephrogenic diabetes insipidus. (Administration of excessive doses of desmopressin resulted in clinically relevant antidiuresis, enhanced by indomethacine and abolished by calcitonine). (Janos Radó’s final comment on Barry Blackwell: The lithium controversy. A historical autopsy. Collated by Olaf Fjetland). Thomas A. Ban: Neuropsychopharmacology in historical perspective. Education in the field in the post-psychopharmacology era. Collated 14. inhn.org.controversies. January 25, 2018.   

Radó J. Desmopressin may counteract polyuria in lithium-induced nephrogenic diabetes insipidus (Review of the literature) inhn.org.controversies. June 27, 2019a.  

Radó J. Renal Toxicity of Lithium in Historical Perspective with Special Reference To Nephrogenic Diabetes Insipidus and its Treatment. inhn.org.controversies. May 2, 2019b. 

Rybakowski J. Final comment: Half a Century of Inspiring Lithium Controversy (Barry Blackwell: The Lithium controversy: A historical autopsy. Collated by Olaf Fjetland). inhn.org.collated. September 30, 2017. 

Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, Geddes JR. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord, 2014;2:15. 

Zhang Y, Hansson K M, Liu T, Kishore B. Genetic Deletion of ADP-activated P2Y12 Receptor Ameliorates Lithium-induced Nephrogenic Diabetes Insipidus in Mice. Acta Physiol (Oxf), 2019;225(2):e13191. 

Zhang Y, Peti-Peterdi J, Müller CE, Carlson NG, Baqi Y, Strasburg DL, Heiney KM, Villanueva K, Kohan DE, Kishore BK. P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus. J Am Soc Nephrol, 2015;26(12):2978-87. 

Zhang Y, Peti-Peterdi J, Brandes A, Riquier-Brison A, Carlson NG, Müller CE, Ecelbarger CM, Kishore BK. Prasugral suppresses development of lithium-induced nephrogenic diabetes insipidus in mice. Purinergic Signal, 2017;13(2):239-48. 

Zhang Y, Pop I, Carlson NG, Kishore BK. Genetic deletion of the P2Y12 receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2 signaling. Am J Physiol Renal Physiol, 2012;302:F70–7.

Zhang Y, Riquier-Brison A, Liu T, Huang Y, Carlson, NG, Peti-Peterdi J, Kishore BK. Genetic Deletion of P2Y12 Receptor Offers Long-Term (5 Months) Protection Against Lithium-Induced Polyuria, Natriuresis, Kaliuresis, and Collecting Duct Remodeling and Cell Proliferation. Front Physiol, 2018;9:1765. 


March 4, 2021