Figure 1.

Diabetic ZSF1 rats recapitulate phenotypic changes of DKD with marked disease improvement by sGC activators

(A) Representation of the importance of heme-containing (native) sGC and heme-free (dysfunctional) form of sGC and its redox equilibrium. sGC stimulator efficacy depends on the ferrous, Fe(II), state of the heme group at the β subunit of sGC, while sGC activators bind directly to oxidized, Fe(III), or heme-free apo form of sGC. Similar to other cardiovascular disorders, DKD is associated with reduced NO bioavailability, increased oxidative stress, and endothelial dysfunction. cGMP, cyclic guanosine monophosphate; DKD, diabetic kidney disease; NO, nitric oxide; NOS, nitric oxide synthase; O₂⁻, superoxide; ONOO⁻, peroxynitrite; sGCact, soluble guanylate cyclase activator; sGCstim, soluble guanylate cyclase stimulator. Adapted from Sandner et al.⁹

(B) Experimental ZSF1 rat model setup. sGCact, soluble guanylate cyclase activator; sGCstim, sGC stimulator.

(C–E) Metabolic (serum cholesterol, glucose, and plasma HbA1c) (C), kidney function (D), and kidney injury markers (E) after 12 study weeks; p values are given for either one-way ANOVA or Kruskal-Wallis test (both Benjamini, Krieger, Yekutieli corrected). Ob, obese; ns, not significant. Color legend as in (B).

(F) Histopathology changes in hematoxylin/eosin (left) and Sirius red/fast green (right) stained kidney sections. Scale bars, 500 μm.

(G) Histopathology scoring; p values are given for Kruskal-Wallis test (Benjamini, Krieger, Yekutieli corrected). Color legend as in (B).