Growth differentiation factor 15 (GDF15) is emerging as valuable biomarker in cardiovascular disease and diabetic kidney disease. Also, GDF15 represents an early response gene induced after tissue injury and studies performed in GDF15 knockout (KO) mice suggest that GDF15 plays a protective role after injury. In the current study, we investigated the role of GDF15 in the development of diabetic kidney damage in type 1 and type 2 models of diabetes. Renal damage was assessed in GDF15 KO mice and wild-type (WT) mice in streptozotocin type 1 and db/db type 2 diabetic models. Genetic deletion of GDF15 augmented tubular and interstitial damage in both models of diabetes, despite similar diabetic states in KO and WT mice. Increased tubular damage in KO animals was associated with increased glucosuria and polyuria in both type 1 and type 2 models of diabetes. In both models of diabetes, KO mice showed increased interstitial damage as indicated by increased α-smooth muscle actin staining and collagen type 1 expression. In contrast, glomerular damage was similarly elevated in diabetic KO and WT mice. In type 1 diabetes, GDF15 KO mice demonstrated increased expression of inflammatory markers. In type 2 diabetes, elevated levels of plasma creatinine indicated impaired kidney function in KO mice. GDF15 protects the renal interstitium and tubular compartment in experimental type 1 and 2 diabetes without affecting glomerular damage.

SUL-compounds are protectants from cold-induced ischemia and mitochondrial dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in α₁-adrenoceptor (α₁-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (−11.9 ± 2.50 mmHg) and its (R)-enantiomer SUL-150 (−13.2 ± 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (−1.33 ± 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 ± 1.71 mL/min to 21.94 ± 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-³H]-prazosin in CHO cells. Docking simulation to the α₁-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α₁-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation.

OBJECTIVE: Although patients with type 2 diabetes (T2D) with nephropathy are at high risk for renal and cardiovascular complications, relevant biomarkers have been poorly identified. Because renal impairment may increase biomarker levels, this potentially confounds associations between biomarker levels and risk. To investigate the predictive value of a biomarker in such a setting, we examined baseline levels of growth differentiation factor-15 (GDF-15), N-terminal prohormone of B-type natriuretic peptide (NTproBNP), and high-sensitivity troponin T (hs-TnT) in relation to renal and cardiovascular risk in T2D patients with nephropathy. RESEARCH DESIGN AND METHODS: Eight hundred sixty-one T2D patients from the sulodexide macroalbuminuria (Sun-MACRO) trial were included in our post hoc analysis. Prospective associations of baseline serum GDF-15, NTproBNP, and hs-TnT with renal and cardiovascular events were determined by Cox multiple regression and C-statistic analysis. Renal base models included albumin-to-creatinine ratio (ACR), serum creatinine, hemoglobin, age, and sex. Cardiovascular base models included diastolic blood pressure, ACR, cholesterol, age, and sex. RESULTS: The mean (±SD) estimated glomerular filtration rate was 33 ± 9 mL/min/1.73 m2, and the median serum concentration for GDF-15 was 3,228 pg/mL (interquartile range 2,345–4,310 pg/mL), for NTproBNP was 380 ng/L (155–989 ng/L), and for hs-TnT was 30 ng/L (20–47 ng/L). In multiple regression analysis, GDF-15 (hazard ratio [HR] 1.83, P = 0.04), NTproBNP (HR 2.34, P = 0.004), and hs-TnT (HR 2.09, P = 0.014) were associated with renal events, whereas NTproBNP (HR 3.45, P < 0.001) was associated with cardiovascular events. The C-statistic was improved by adding NTproBNP and hs-TNT to the renal model (0.793 vs. 0.741, P = 0.04). For cardiovascular events, the C-statistic was improved by adding NTproBNP alone (0.722 vs. 0.658, P = 0.018). CONCLUSIONS: Biomarkers GDF-15, NTproBNP, and hs-TnT associate independently with renal risk, whereas NTproBNP independently predicts cardiovascular risk.

Cystathionine-β-synthase (CBS) is highly expressed in the liver, and deficiencies in Cbs lead to hyperhomocysteinemia (HHCy) and disturbed production of antioxidants such as hydrogen sulfide. We therefore hypothesized that liver-specific Cbs deficient (LiCKO) mice would be particularly susceptible to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced by a high-fat high-cholesterol (HFC) diet; LiCKO and controls were split into eight groups based on genotype (con, LiCKO), diet (normal diet, HFC), and diet duration (12 weeks, 20 weeks). LiCKO mice displayed intermediate to severe HHCy. Plasma H₂O₂ was increased by HFC, and further aggravated in LiCKO. LiCKO mice fed an HFC diet had heavier livers, increased lipid peroxidation, elevated ALAT, aggravated hepatic steatosis, and inflammation. LiCKO mice showed decreased L-carnitine in the liver, but this did not result in impaired fatty acid oxidation. Moreover, HFC-fed LiCKO mice demonstrated vascular and renal endothelial dysfunction. Liver and endothelial damage correlated significantly with systemic ROS status. In conclusion, this study demonstrates an important role for CBS in the liver in the development of NAFLD, which is most probably mediated through impaired defense against oxidative stress.

Diabetic nephropathy is still a common complication of type 2 diabetes mellitus (T2DM) and improvement of endothelial dysfunction (ED) and inhibition of reactive oxygen species (ROS) are considered important targets for new therapies. Recently, we developed a new class of compounds (Sul compounds) which inhibit mitochondrial ROS production. Here, we tested the therapeutic effects of Sul-121 on ED and kidney damage in experimental T2DM. Diabetic db/db and lean mice were implanted with osmotic pumps delivering Sul-121 (2.2 mg/kg/day) or vehicle from age 10 to 18 weeks. Albuminuria, blood pressure, endothelial mediated relaxation, renal histology, plasma creatinine, and H₂O₂ levels were assessed. Sul-121 prevented progression of albuminuria and attenuated kidney damage in db/db, as evidenced by lower glomerular fibronectin expression (~50%), decreased focal glomerular sclerosis score (~40%) and normalization of glomerular size and kidney weight. Further, Sul-121 restored endothelium mediated vasorelaxation through increased production of Nitric Oxide production and normalized plasma H₂O₂ levels. Sul-121 treatment in lean mice demonstrated no observable major side-effects, indicating that Sul-121 is well tolerated. Our data show that Sul-121 inhibits progression of diabetic kidney damage via a mechanism that involves restoration of endothelial function and attenuation of oxidative stress.