Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

Riociguat is a soluble guanylate cyclase (sGC) activator that increases the levels of cyclic guanosine monophosphate (cGMP). cGMP is known to play a key role in regulating kidney function. This research sought to investigate the possible protective effects of riociguat on the kidneys in the context of chronic kidney disease (CKD). CKD was induced in male Wistar rats through adenine administration. A total of 24 rats were allocated into four groups and administered treatments over a period of 35 days. Group 1 received a normal diet and a vehicle (carboxymethylcellulose (0.5%)), serving as the control. Group 2 received adenine (0.25% w/w) in the feed and a vehicle. Groups 3 and 4 received adenine in the feed (0.25% w/w) plus riociguat (3 mg/kg/day) and riociguat (10 mg/kg/day), respectively. Adenine administration significantly elevated systolic blood pressure, plasma creatinine, urea, and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, adenine reduced creatinine clearance and increased the urinary albumin-to-creatinine ratio and urinary N-Acetyl-β-D-Glucosaminidase (NAG). Histopathologically, adenine caused renal tubular necrosis and fibrosis. Furthermore, adenine elevated the plasma concentration of interleukins (IL-1β and IL-6) and tumor necrosis factor-alpha (TNF-α). Adenine significantly increased renal malondialdehyde (MDA) and reduced glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC). Treatment with riociguat attenuated adenine-induced hypertension, improved kidney function, and ameliorated histopathological changes. Riociguat also reduced kidney injury markers, inflammation, and renal oxidative stress. The renoprotective effect of riociguat is probably due to anti-inflammatory and antioxidant actions. This indicates that riociguat may have the potential to slow the progression of kidney damage in chronic kidney disease (CKD).

The recent genome-wide analysis of carotid–femoral pulse wave velocity (PWV) identified a significant locus within the 14q32.2 gene desert. Gene regulatory elements for the transcriptional regulator B-cell CLL/lymphoma 11B (BCL11B) are within this locus and an attractive target for the gene association. We investigated the functional impact of these gene desert SNPs on BCL11B transcript in human aorta to characterize further its role in aortic stiffness. To do this, we used a large repository of aortic tissues (n = 185) from an organ transplant program and assessed ex vivo stiffness of the aortic rings. We tested association of three lead SNPs from the GWAS meta-analysis with ex vivo aortic stiffness and BCL11B aortic mRNA expression: rs1381289 and rs10782490 SNPs associated significantly with PWV and showed allele-specific differences in BCL11B mRNA. The risk alleles associated with lower BCL11B expression, suggesting a protective role for BCL11B. Despite strong association, we could not detect BCL11B protein in the human aorta. However, qPCR for CD markers showed that BCL11B transcript correlated strongly with markers for activated lymphocytes. Our data confirm the significance of the 14q32.2 region as a risk locus for aortic stiffness and an upstream regulator of BCL11B. The BCL11B transcript detected in the human aorta may reflect lymphocyte infiltration, suggesting that immune mechanisms contribute to the observed association of BCL11B with aortic stiffness.

Background: Cisplatin (CP), a platinum-based chemotherapeutic agent, is widely used to treat cancer but causes nephrotoxicity. Riociguat, a soluble guanylate cyclase (sGC) stimulator that enhances the nitric oxide–sGC–cGMP signaling pathway, was investigated for its potential protective effects against cisplatin-induced nephrotoxicity. Materials and Methods: Rats were randomly divided into four equal groups (six rats each) and treated for nine consecutive days. The first and second groups were given oral carboxymethylcellulose 0.5% (vehicle) for 9 days, and on day 6 were injected intraperitoneally with saline or CP, respectively. The third and fourth groups were treated orally with two doses of riociguat (3 and 10 mg/kg/day) for 9 days, and received intraperitoneal injections of CP on day 6. Blood, urine, and kidney tissues were analyzed 24 h after the last treatment. Results: CP significantly elevated the markers of kidney function, including uric acid, serum creatinine, and urea. CP also caused histological kidney damage. Antioxidant markers, including catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), and total antioxidant capacity (TAC) were significantly reduced, while inflammatory cytokines (IL-1β, IL-6, and TNF-α) and lipid peroxidation (MDA) were markedly increased. Riociguat improved kidney structure and significantly reduced kidney function markers, MDA, and inflammatory cytokines while restoring GR, TAC, SOD, and CAT activities. Conclusions: These results indicate that riociguat exerts protection of the kidneys from CP-caused kidney damage by antioxidation and anti-inflammation. Riociguat may have potential as an adjunct therapy to mitigate CP-associated nephrotoxicity.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are associated with significant morbidity and mortality. Their progression is driven by inflammation, oxidative stress, and apoptosis. In this study, we examined the effects of nine different combinations of gum acacia (GA), melatonin, betaine, and flaxseed—used in pairs or trios—on adenine-induced CKD in streptozotocin (STZ)-induced diabetic rats. Rats treated with adenine and STZ exhibited significant hyperglycemia and CKD manifestations such as elevated plasma levels of cystatin C and indoxyl sulfate, increased urinary levels of N-acetyl-β-D-glucosaminidase (NAG) and NAG/creatinine ratio, and reduced creatinine clearance. Additionally, there was a significant decrease in renalase activity and urine osmolality, alongside a significant increase in IL-1β, IL-6, and TNF-α levels and a decrease in IL-10 levels. Oxidative stress biomarkers including superoxide dismutase, glutathione reductase, total antioxidant capacity, and catalase activities were also significantly impaired. These findings were supported by histopathological changes consistent with CKD. Treatment with the combinations of two or three agents alleviated most of these changes to varying degrees. Notably, the GA–melatonin–betaine combination demonstrated the most significant improvement across all the parameters along with the preservation of the kidney tissue structure. These improvements may partially be explained by the enhanced glycemic control achieved by this combination, in addition to possible synergistic molecular, pharmacokinetic, and pharmacodynamic interactions. These findings support the potential of this combination to attenuate the progression of CKD in the setting of diabetes. However, further mechanistic studies, pharmacokinetic profiling, and long-term toxicity data are necessary to validate its efficacy and safety for clinical use.