Activation of G protein-coupled estrogen receptor 1 ameliorates proximal tubular injury and proteinuria in Dahl salt-sensitive female rats

Abstract

Recent evidence indicates a crucial role for G protein-coupled estrogen receptor 1 (GPER1) in the maintenance of cardiovascular and kidney health in females. The current study tested whether GPER1 activation ameliorates hypertension and kidney damage in female Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. Adult female rats were implanted with telemetry transmitters for monitoring blood pressure and osmotic minipumps releasing G1 (selective GPER1 agonist, 400 μg/kg/day, intraperitoneal) or vehicle. Two weeks after pump implantation, rats were shifted from a normal salt diet (NS, 0.4% NaCl) to a matched HS diet (4.0% NaCl) for 2 weeks. 24-hour urine samples were collected during both diet periods and urinary markers of kidney injury were assessed. Histological assessment of kidney injury was conducted after the 2-week HS diet period. Compared with values during the NS diet, 24-hour mean arterial pressure markedly increased in response to HS, reaching similar values in vehicle-treated and G1-treated rats. HS also significantly increased urinary excretion of protein, albumin, nephrin (podocyte damage marker) and KIM-1 (proximal tubule injury marker) in vehicle-treated rats. Importantly, G1 treatment prevented the HS-induced proteinuria, albuminuria and increase in KIM-1 excretion but not nephrinuria. Histological analysis revealed that HS-induced glomerular damage did not differ between groups. However, G1 treatment preserved proximal tubule brush border integrity in HS-fed rats. Collectively, our data suggest that GPER1 activation protects against HS-induced proteinuria and albuminuria in female Dahl SS rats by preserving proximal tubule brush border integrity in a blood pressure-independent manner.

Emerging Roles for G Protein-Coupled Estrogen Receptor 1 in Cardio-Renal Health: Implications for Aging

“…Using methotrexate-induced nephrotoxicity models in human renal epithelial cells, Kurt et al showed that co-incubation of cells with either E 2 or G-1 reduces the high levels of interleukin-1β and interleukin-6 induced by methotrexate [189]. However, our studies indicate that although G-1 treatment effectively prevented salt-induced proteinuria and proximal tubular injury in female Dahl salt sensitive rats, it did not decrease salt-induced immune cell accumulation in the kidney [213]. These results highlight the need for further research to confirm the immune effects of GPER1 activation in cardiovascular and renal systems and to elucidate the potential role of GPER1 signaling in inflammageing.…”

“…Earlier studies reported that ovariectomy increases levels of renal inflammatory markers in Dahl salt-sensitive female rats [248], hinting at the protective role of the female sex hormone against hypertension and end-organ kidney damage. Moreover, we reported that G-1 ameliorates kidney damage in high salt-fed female Dahl salt-sensitive via preservation of the proximal tubule brush border integrity [213]. The definitive role of GPER1 in CKD initiation and progression is not entirely known yet, but evidence supports its role as a protective mechanism against kidney damage, independent from blood pressure changes.…”

Does G Protein-Coupled Estrogen Receptor 1 Contribute to Cisplatin-Induced Acute Kidney Injury in Male Mice?

“…Evidence points to a critical role for the novel estrogen receptor GPER1 in the maintenance of cardiovascular and kidney health [ 11 , 16 , 17 , 24 , 29 , 40 ]. To date, the contribution of GPER1 to Cp-induced AKI is unknown.…”

“…These findings are consistent with those from studies by Hutchens and colleagues conducted in female mice [ 41 ], showing that estradiol (E 2 ) treatment attenuates acute renal injury following cardiac arrest and cardiopulmonary resuscitation irrespective of GPER1 gene deletion. In contrast, it has been demonstrated that GPER1 activation by G1 reduces renal injury in female Dahl salt-sensitive rats [ 17 ], mRen2.Lewis rats [ 16 ], and Sprague Dawley rats [ 18 ]. Whether pharmacological interventions using the selective GPER1 agonists/antagonists, rather than genetic approaches, induce a renoprotective effect against Cp-induced AKI remains to be tested.…”

“…Of note, within the kidney, GPER1 is expressed in the renal tubules as well as in renal epithelial cells [ 15 , 16 ]. Recent evidence points to a renal protective potential of GPER1 in nephropathies evoked by salt-induced hypertension [ 16 , 17 ] and ischemia reperfusion [ 18 ] in female rats. However, the involvement of GPER1 signaling in Cp-induced nephrotoxicity/AKI has not been explored.…”