Glucagon receptor agonist aggravates a murine model of Balkan nephropathy

Combining agonists of glucagon receptors (GCGRA) and GLP1 receptors (GLP1RA) is explored for treatment of obesity, but little is known on kidney protection by GCGRA. To gain further insights, mice with Western diet-induced obesity were first treated for 18 days with a GLP1RA or a GCGRA, and then exposed to tubule-toxic aristolochic acid (AA), a murine model of Balkan nephropathy. Prior to AA application, GLP1RA reduced food intake by ~30% and body weight by ~16% vs. vehicle with no significant changes in non-fasted blood glucose levels or plasma creatinine or urea. GCGRA reduced body weight by ~6% without changing food intake or plasma creatinine associated with hyperglycemia (230 vs 143 mg/dl) and 14% lower plasma urea concentrations versus vehicle. Among AA treated groups, GLP1RA improved some parameters but overall did not robustly attenuate kidney injury. GCGRA enhanced kidney mRNA expression of Rev-Erba, an inhibitory transcription factor previously implicated in glucagon-induced suppression of glucose transporter SGLT2, suppression of inflammation/fibrosis, but aggravation of AA-induced kidney injury. GCGRA indeed reduced kidney expression of Sglt2, inflammatory markers (incl. Il6, Ccl2, Tnfa and histological inflammation score), and also tubular injury marker KIM-1 and profibrotic Col1a1 and Sirius red fibrosis staining. GCGRA, however, sensitized towards AA-induced kidney injury based on reduction in body weight and hematocrit, and higher levels of plasma creatinine, urea and ammonia, kidney NGAL and p21 mRNA expression, histological acute tubular injury score, and mortality. In conclusion, GCGR agonism can aggravate a murine model of Balkan nephropathy, possibly involving Rev-Erba-induced gene suppression.