Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

Aliskiren: Direct Renin Inhibitor Baru pada Terapi Hipertensi

Hipertensi merupakan kondisi ketika tekanan darah meningkat secara kronis. Mengacu pada hasil Riset Kesehatan Dasar (Riskesdas), Bali memiliki proporsi hipertensi sebesar 19,9%. Beberapa studi epidemiologis menyebutkan bahwa risiko kerusakan berbagai organ vital secara langsung berkorelasi dengan peningkatan tekanan darah. Oleh karena itu, diperlukan keteraturan dalam mengontrol dan juga meminum obat antihipertensi. Obat antihipertensi yang umum digunakan saat ini adalah angiotensin converting enzyme inhibitor (ACEI) dan angiotensin receptor blocker (ARB). Akan tetapi, temuan sebelumnya menyatakan bahwa ACEI dan ARB belum sepenuhnya efektif dalam menurunkan tekanan darah. Untuk mengatasi kelemahan tersebut, ditemukan direct renin inhibitor baru yaitu aliskiren. Aliskiren dapat memblokade renin-angiotensin-aldosterone system (RAAS) pada level tertinggi, sehingga kemampuan aliskiren dalam menurunkan tekanan darah tidak dapat diragukan lagi. Aliskiren mampu menghambat konversi angiotensinogen menjadi angiotensin I, sehingga dapat menurunkan tekanan darah secara berkelanjutan.

Aliskiren and the dual complement inhibition concept

In this issue of Clinical Kidney Journal, Plasse et al. report on the use of high-dose aliskiren as an adjunct therapy in a patient treated with eculizumab for haemolytic uraemic syndrome (HUS). This follows the recent description of the complement factor 3 (C3) activating activity of the enzyme renin and the successful therapeutic use of the direct renin inhibitor aliskiren in three cases of C3 glomerulopathy/dense deposit disease. We discuss the potential clinical and pathophysiological implications of these reports on nephropathies linked to complement, from HUS to C3 glomerulopathy to immunoglobulin A nephropathy as well as the concept of dual complement inhibition for kidney disease.

Normalizing Plasma Renin Activity in Experimental Dilated Cardiomyopathy: Effects on Edema, Cachexia, and Survival

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A–D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.