Lack Of Atrial Natriuretic Peptide Aggravates Glomerular Disease In Type 1 Diabetic Nephropathy

Introduction: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and DKD patients have a significantly higher risk of developing cardiovascular disease. Some studies have suggested the role of the Atrial Natriuretic Peptide (ANP) in DKD development. ANP is a cardiac hormone that regulates renal salt/water homeostasis and plays a major role in renal hemodynamics. We hypothesized here that ANP plays a critical role in T1DKD, playing a potential protective role in podocytes of the glomeruli. Methods: We used the ANP knock-out (SS NPPA-/- ) rat on the Dahl Salt-Sensitive (Dahl SS) background injected with streptozotocin (STZ; 75mg/kg) as a model of T1DKD. At 9-10 weeks of age, male SS NPPA-/- and Dahl SS wild-type (SS WT ) rats were i.p. injected with either STZ or vehicle. Baseline, midpoint, and endpoint blood glucose, urine, and body weights were collected. Glomerular filtration rate (GFR) was assessed before animals were. Glomerular injury was scored blindly on a scale from 0-4 (0 = healthy glomerulus, 4 = severely sclerosed) in Masson Trichrome stained kidneys. One-way ANOVA through Origin 2019b was used for statistical analysis. Results: STZ- SS WT and STZ-SS NPPA-/- groups exhibited similar body weight (237.8 ± 18.9 vs. 234.5 ± 10.03 g, respectively), two-kidney weight to body weight ratio (32.1 ± 1.6 vs. 29.4 ± 1.6 mg/g, respectively), and endpoint blood glucose levels (>650 mg/dL). Interestingly, we observed a significantly higher heart to body weight ratio for the STZ-SS NPPA-/- vs STZ- SS WT rats (7.0 ± 0.33 vs. 5.1 ± 0.07 mg/g, respectively, p<0.05). STZ- SS WT and STZ-SS NPPA-/- had similar diuresis (54.4 ± 2.8 vs. 52.5 ± 4.01 mL/24hr/100gTBW, respectively). Importantly, histological analysis displayed a more profound glomerular injury in the STZ-SS NPPA-/- when they were compared to STZ- SS WT (3.4 ± 0.02 vs. 3.2 ± 0.03 au, respectively, p<0.05). Conclusion: Thus far the data suggest that lack of ANP has a detrimental impact on DKD-related renal tissue damage, specifically, glomerular disease progression. Future studies will provide mechanistic insight into the role of ANP in oxidative stress and assess the role of ANP in nitric oxide production and calcium transients in the podocyte.