Description:
<jats:p>Cell stress leads to cellular release of mitochondrial succinate and activation of its receptor, the SUCNR1, in the renal macula densa is essential for DMI‐related renin release and hypertension. Obesity‐induced DMII and Chronic Kidney Disease (CKD) development is aggravated by hypertension and goes with cell stress in adipose/kidney tissue and macrophages, which express SUCNR1. Here we tested the role of SUCNR1 in obesity‐induced DMII and CKD. Wild‐type and SUCNR1‐/‐ mice fed for 16 weeks with a high fat diet (HFD) revealed a similar gain in total, adipose and kidney weight as compared to low fat diet (LFD) groups, but the gain was higher for liver and heart in wt than SUCNR1‐/‐ mice. Starving glucose levels were similarly increased in both HFD groups, but SUCNR1‐/‐ mice had a better glucose tolerance test response, indicating less insulin resistance in SUCNR1‐/‐ mice. For both HFD groups, blood sodium and urine volumes were similarly reduced, whereas GFR was similarly increased. Importantly, HFD wt mice showed albuminuria and glomerular/interstitial expression of collagen IV, indicative of fibrosis, which was not observed in HFD SUCNR1‐/‐ mice, nor LFD groups. Hypertensive patients and rodent models showed elevated urinary succinate levels, indicating that the renal SUCNR1 is activated in hypertension.</jats:p><jats:p>Together, our data reveal that SUCNR1 activation contributes to obesity‐induced DM and CKD development and, if similar in humans, that SUCNR1 blockers may form novel therapeutics for the treatment of these common disorders.</jats:p>