The Succinate Receptor 1 is a Physiological Regulator of the Renin‐Angiontensin Aldosterone System

Abstract

It has been shown that oxidative cell stress in diabetes type I (DMI) induces tubular release of mitochondrial succinate and that subsequent activation of the SUCNR1 in the juxta‐glomerular apparatus is needed for renin release and DMI‐induced hypertension. Here, we tested whether the SUCNR1 also has a physiological role in renal water and electrolyte handling.Blood and urine analysis of wild‐type and SUCNR1‐/‐ mice showed that loss of SUCNR1 increased sodium and albumin excretion, and reduced renal renin and plasma angiotensin II (AngII) levels. Immunoblotting revealed decreased proximal tubular and inversely related medullary abundance of sodium‐hydrogen exchanger (NHE)‐3, and decreased abundance of the epithelial sodium channel ENaC. Nitric Oxide (NO) release, and fractional excretion of urea and water were increased, coinciding with reduced AQP2 abundance. With an unchanged overall morphology, wet, but not dry, weights of kidneys of SUCNR1‐/‐ mice were significantly higher than of wild‐type littermates.Our data reveal that the SUCNR1 is essential for the physiological maintenance of renin and AngII levels, and proper proximal tubule and collecting duct sodium reabsorption. Albumin release may be secondary to the decreased cortical NHE3 expression in proximal tubules, due to reduced AngII levels. Increased NO may underlie water loss.The increased wet kidney mass is likely due to tubular dilation due to increased tubular pressure because of life‐long diuresis. Our data thus indicate that the mammalian SUCNR1 is a physiological regulator of water and volume homeostasis.