Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions.

Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes.

Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

Endothelial reactive oxygen-forming NADPH oxidase 5 is a possible player in diabetic aortic aneurysm but not atherosclerosis.

Atherosclerosis and its complications are major causes of cardiovascular morbidity and death. Apart from risk factors such as hypercholesterolemia and inflammation, the causal molecular mechanisms are unknown. One proposed causal mechanism involves elevated levels of reactive oxygen species (ROS). Indeed, early expression of the ROS forming NADPH oxidase type 5 (Nox5) in vascular endothelial cells correlates with atherosclerosis and aortic aneurysm. Here we test the pro-atherogenic Nox5 hypothesis using mouse models. Because Nox5 is missing from the mouse genome, a knock-in mouse model expressing human Nox5 in its physiological location of endothelial cells (eNOX5ki/ki) was tested as a possible new humanised mouse atherosclerosis model. However, whether just on a high cholesterol diet or by crossing in aortic atherosclerosis-prone ApoE-/- mice with and without induction of diabetes, Nox5 neither induced on its own nor aggravated aortic atherosclerosis. Surprisingly, however, diabetic ApoE-/- x eNOX5ki/ki mice developed aortic aneurysms more than twice as often correlating with lower vascular collagens, as assessed by trichrome staining, without changes in inflammatory gene expression, suggesting that endothelial Nox5 directly affects extracellular matrix remodelling associated with aneurysm formation in diabetes. Thus Nox5-derived reactive oxygen species are not a new independent mechanism of atherosclerosis but may enhance the frequency of abdominal aortic aneurysms in the context of diabetes. Together with similar clinical findings, our preclinical target validation opens up a first-in-class mechanism-based approach to treat or even prevent abdominal aortic aneurysms.

Reconsidering the Chemical Nature of Strand Breaks Derived from Abasic Sites in Cellular DNA: Evidence for 3'-Glutathionylation.

The hydrolytic loss of coding bases from cellular DNA is a common and unavoidable reaction. The resulting abasic sites can undergo ß-elimination of the 3'-phosphoryl group to generate a strand break with an electrophilic α,ß-unsaturated aldehyde residue on the 3'-terminus. The work reported here provides evidence that the thiol residue of the cellular tripeptide glutathione rapidly adds to the alkenal group on the 3'-terminus of an AP-derived strand break. The resulting glutathionylated adduct is the only major cleavage product observed when ß-elimination occurs at an AP site in the presence of glutathione. Formation of the glutathionylated cleavage product is reversible, but in the presence of physiological concentrations of glutathione, the adduct persists for days. Biochemical experiments provided evidence that the 3'-phosphodiesterase activity of the enzyme apurinic/apyrimidinic endonuclease (APE1) can remove the glutathionylated sugar remnant from an AP-derived strand break to generate the 3'OH residue required for repair via base excision or single-strand break repair pathways. The results suggest that a previously unrecognized 3'glutathionylated sugar remnant─and not the canonical α,ß-unsaturated aldehyde end group─may be the true strand cleavage product arising from ß-elimination at an abasic site in cellular DNA. This work introduces the 3'glutathionylated cleavage product as the major blocking group that must be trimmed to enable repair of abasic site-derived strand breaks by the base excision repair or single-strand break repair pathways.

Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways.

Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). Here, we provide key findings demonstrating the predominant pathological role of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) in DKD, independent of the previously characterized NOX4 pathway. In patients with diabetes, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors early growth response 1 (EGR-1), protein kinase C-α (PKC-α), and a key metabolic gene involved in redox balance, thioredoxin-interacting protein (TXNIP). In preclinical models of DKD, overexpression of NOX5 in Nox4-deficient mice enhances kidney damage by increasing albuminuria and augmenting renal fibrosis and inflammation via enhanced ROS formation and the modulation of EGR1, TXNIP, ERK1/2, PKC-α, and PKC-ε. In addition, the only first-in-class NOX inhibitor, GKT137831, appears to be ineffective in the presence of NOX5 expression in diabetes. In vitro, silencing of NOX5 in human mesangial cells attenuated upregulation of EGR1, PKC-α, and TXNIP induced by high glucose levels, as well as markers of inflammation (TLR4 and MCP-1) and fibrosis (CTGF and collagens I and III) via reduction in ROS formation. Collectively, these findings identify NOX5 as a superior target in human DKD compared with other NOX isoforms such as NOX4, which may have been overinterpreted in previous rodent studies.

Diabetic Kidney Disease: From Pathogenesis to Novel Treatment Possibilities.

One of the microvascular complications of diabetes is diabetic kidney disease (DKD), often leading to end stage renal disease (ESRD) in which patients require costly dialysis or transplantation. The silent onset and irreversible progression of DKD are characterized by a steady decline of the estimated glomerular filtration rate, with or without concomitant albuminuria. The diabetic milieu allows the complex pathophysiology of DKD to enter a vicious cycle by inducing the synthesis of excessive amounts of reactive oxygen species (ROS) causing oxidative stress, inflammation, and fibrosis. As no cure is available, intensive research is required to develop novel treatments possibilities. This chapter provides an overview of the important pathomechanisms identified in diabetic kidney disease, the currently established therapies, as well as recently developed novel therapeutic strategies in DKD.

Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System.

Abasic sites are common in cellular and synthetic DNA. As a result, it is important to characterize the chemical fate of these lesions. Amine-catalyzed strand cleavage at abasic sites in DNA is an important process in which conversion of small amounts of the ring-opened abasic aldehyde residue to an iminium ion facilitates ß-elimination of the 3'-phosphoryl group. This reaction generates a trans-α,ß-unsaturated iminium ion on the 3'-terminus of the strand break as an obligate intermediate. The canonical product expected from amine-catalyzed cleavage at an AP site is the corresponding trans-α,ß-unsaturated aldehyde sugar remnant resulting from hydrolysis of this iminium ion. Interestingly, a handful of studies have reported noncanonical 3'-sugar remnants generated by amine-catalyzed strand cleavage, but the formation and properties of these products are not well-understood. To address this knowledge gap, a nucleoside system was developed that enabled chemical characterization of the sugar remnants generated by amine-catalyzed ß-elimination in the 2-deoxyribose system. The results predict that amine-catalyzed strand cleavage at an AP site under physiological conditions has the potential to reversibly generate noncanonical cleavage products including cis-alkenal, 3-thio-2,3-dideoxyribose, and 2-deoxyribose groups alongside the canonical trans-alkenal residue on the 3'-terminus of the strand break. Thus, the model reactions provide evidence that the products generated by amine-catalyzed strand cleavage at abasic sites in cellular DNA may be more complex that commonly thought, with trans-α,ß-unsaturated iminium ion intermediates residing at the hub of interconverting product mixtures. The results expand the list of possible 3'-sugar remnants arising from amine-catalyzed cleavage of abasic sites in DNA that must be chemically or enzymatically removed for the completion of base excision repair and single-strand break repair in cells.

Unexpected Complexity in the Products Arising from NaOH-, Heat-, Amine-, and Glycosylase-Induced Strand Cleavage at an Abasic Site in DNA.

Hydrolytic loss of nucleobases from the deoxyribose backbone of DNA is one of the most common unavoidable types of damage in synthetic and cellular DNA. The reaction generates abasic sites in DNA, and it is important to understand the properties of these lesions. The acidic nature of the α-protons of the ring-opened abasic aldehyde residue facilitates the ß-elimination of the 3'-phosphoryl group. This reaction is expected to generate a DNA strand break with a phosphoryl group on the 5'-terminus and a trans-α,ß-unsaturated aldehyde residue on the 3'-terminus; however, a handful of studies have identified noncanonical sugar remnants on the 3'-terminus, suggesting that the products arising from strand cleavage at apurinic/apyrimidinic sites in DNA may be more complex than commonly thought. We characterized the strand cleavage induced by the treatment of an abasic site-containing DNA oligonucleotide with heat, NaOH, piperidine, spermine, and the base excision repair glycosylases Fpg and Endo III. The results showed that under multiple conditions, cleavage at an abasic site in a DNA oligomer generated noncanonical sugar remnants including cis-α,ß-unsaturated aldehyde, 2-deoxyribose, and 3-thio-2,3-dideoxyribose products on the 3'-terminus of the strand break.

Waste seeds of Mangifera indica, Artocarpus heterophyllus, and Schizizium commune as biochar for heavy metal removal from simulated wastewater.

The threat of arsenic contamination in water is a challenging issue worldwide. Millions of people utilize untreated groundwater having high levels of arsenic in developing countries. Design Expert 6.0.8 has been used to design experiments and carried out statistical analysis for optimization of different parameters. It is of prime importance to develop cheap environment friendly bio-sorbent for protecting health of the poor from ill effects of arsenic. In the present investigation, we prepared bio-sorbent from the solid waste seed biomass of Mangifera indica (M), Artocarpus heterophyllus (JF), and Schizizium commune (JP). The characterization of bio-sorbents has been done by using different techniques namely FTIR and XRD. Arsenic concentration was estimated using ICP and adsorption parameters optimized for pH, adsorbent dose, and initial arsenic concentration. At pH 8.4, kinetics study of arsenic removal was M (94%), JF (93%), and JP (92%) for initial concentration of 2.5 ppm. The adsorption kinetics was well explained by Freundlich model and pseudo-second reaction order. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13399-021-02078-5.

Adverse renal effects of NLRP3 inflammasome inhibition by MCC950 in an interventional model of diabetic kidney disease.

Activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome has been reported in diabetic complications including diabetic kidney disease (DKD). However, it remains unknown if NLRP3 inhibition is renoprotective in a clinically relevant interventional approach with established DKD. We therefore examined the effect of the NLRP3-specific inhibitor MCC950 in streptozotocin-induced diabetic mice to measure the impact of NLRP3 inhibition on renal inflammation and associated pathology in DKD. We identified an adverse effect of MCC950 on renal pathology in diabetic animals. Indeed, MCC950-treated diabetic animals showed increased renal inflammation and macrophage infiltration in association with enhanced oxidative stress as well as increased mesangial expansion and glomerulosclerosis when compared with vehicle-treated diabetic animals. Inhibition of the inflammasome by MCC950 in diabetic mice led to renal up-regulation of markers of inflammation (Il1ß, Il18 and Mcp1), fibrosis (Col1, Col4, Fn1, α-SMA, Ctgf and Tgfß1) and oxidative stress (Nox2, Nox4 and nitrotyrosine). In addition, enhanced glomerular accumulation of pro-inflammatory CD68 positive cells and pro-oxidant factor nitrotyrosine was identified in the MCC950-treated diabetic compared with vehicle-treated diabetic animals. Collectively, in this interventional model of established DKD, NLRP3 inhibition with MCC950 did not show renoprotective effects in diabetic mice. On the contrary, diabetic mice treated with MCC950 exhibited adverse renal effects particularly enhanced renal inflammation and injury including mesangial expansion and glomerulosclerosis.

Sustainable removal of arsenic from simulated wastewater using solid waste seed pods biosorbents of Cassia fistula L.

The present investigation is focused to develop a new type of solid waste based biosorbent, derived from the Cassia fistula pod biomass. The prepared biosorbent has been characterized through different techniques including field emission scanning electron microscopy, fourier transform infrared spectroscope and X-ray diffraction to investigate the physiochemical properties which are potential for the bioadsorbent application. The experiments have been performed considering four parameters namely; pH, biosorbent dose, initial concentration of As+3 and duration in the batch reactor. The experimental results have been analyzed using the design-expert software for the optimization of different parameters. The maximum removal of arsenic could be achieved ∼91% whereas monolayer adsorption capacity is found to be 1.13 mg g-1 in 80 min at pH 6.0 and 30 °C by using 60 mg dose of bioadsorbent. The arsenic adsorption behavior of the bio-adsorbent has been well interpreted in terms of pseudo-first order and Freundlich model.

Dyslipidemia, Diabetes and Atherosclerosis: Role of Inflammation and ROS-Redox-Sensitive Factors.

The prevalence of diabetes is growing at an alarming rate with increased disability, morbidity, and often premature mortality because of the various complications of this disorder. Chronic hyperglycemia, dyslipidemia, and other metabolic alterations lead to the development and progression of macro- and microvascular complications of diabetes including cardiovascular, retinal and kidney disease. Despite advances in glucose and lipid lowering treatments, a large number of diabetic individuals develop one or more types of these complications, ultimately leading to end-organ damage over the time. Atherosclerosis is the major macro-vascular complications of diabetes and the primary underlying cause of cardiovascular disease (CVD) posing heavy burden on the health care system. In this review, we discuss the involvement of dyslipidemia in the progression of atherosclerosis by activating the pro-inflammatory cytokines and oxidative stress-related factors. In addition, we also provide information on various pharmacological agents that provides protection against diabetic atherosclerosis by reducing inflammation and oxidative stress.

Formation and Repair of an Interstrand DNA Cross-Link Arising from a Common Endogenous Lesion.

Interstrand DNA cross-links (ICLs) are cytotoxic because they block the strand separation required for read-out and replication of the genetic information in duplex DNA. The unavoidable formation of ICLs in cellular DNA may contribute to aging, neurodegeneration, and cancer. Here, we describe the formation and properties of a structurally complex ICL derived from an apurinic/apyrimidinic (AP) site, which is one of the most common endogenous lesions in cellular DNA. The results characterize a cross-link arising from aza-Michael addition of the N2-amino group of a guanine residue to the electrophilic sugar remnant generated by spermine-mediated strand cleavage at an AP site in duplex DNA. An α,ß-unsaturated iminium ion is the critical intermediate involved in ICL formation. Studies employing the bacteriophage φ29 polymerase provided evidence that this ICL can block critical DNA transactions that require strand separation. The results of biochemical studies suggest that this complex strand break/ICL might be repaired by a simple mechanism in which the 3'-exonuclease action of the enzyme apurinic/apyrimidinic endonuclease (APE1) unhooks the cross-link to initiate repair via the single-strand break repair pathway.

Low-cost biochar adsorbents prepared from date and delonix regia seeds for heavy metal sorption.

In this study, low-cost biochar as bio-adsorbents derived from locally accessible delonix regia seed and date seeds were explored for heavy metal environmental cleaning. These prepared biochars were characterized by proximate and elemental analyses, CHNS/O analysis, Fourier-transformed infrared spectroscopy and thermo-gravitational methods. Bio-sorbent's ability to adsorb arsenic ions in synthetic wastewater was studied and optimized at varying solution pH, adsorbent dose, and starting metal concentrations. Experimentation and optimization studies were also carried out with the help of Design-software 6.0.8. The trials were designed by using response-surface methods, which includes three components and stages of Box-Behnken design. Date seeds derived-biochars eliminated 95% of arsenic from synthetic wastewater, whereas Delonix regia seeds removed 93.8%. The kinetics, isotherms and mechanism of As adsorption were also postulated. This study proposes that these seed's biochars might be employed as an effective, low-cost, and environmentally friendly adsorbent to remove heavy metals from the environment.

Java plum and amaltash seed biomass based bio-adsorbents for synthetic wastewater treatment.

Biomass of Java plum (JP) and amaltash (AT) seeds were employed to remove arsenic from synthetic wastewater, cost effectively. The prepared biomasses were characterized by FE-SEM, EDX, FTIR, XRD, and ICP techniques. Experimentation the optimization study has been carried out by using Design-software 6.0.8. Response surface methodology has been applied to design the experiments where we have used three factors and three levels Box-Behnken design (BBD). Arsenic removal ability of bio-sorbents was evaluated and optimized by varying pH, adsorbent dose concentration of arsenic in synthetic wastewater. For 2.5 mg/L arsenic concentration and 80 mg adsorbent dose at pH 8.8 Java plum seeds (JP) based bio-adsorbent removed ∼93% and amaltash seeds (AT) based bio-adsorbent removed ∼91% arsenic from synthetic wastewater. The adsorption behaviour better explained following Freundlich model (R2 = 0.99) compared to Temkin model (R2 = 0.986) for As (III) ions. The adsorption capacity was 1.45 mg g-1 and 1.42 mg g-1 for JP and AT, respectively after 80 min under optimal set of condition. The adsorption kinetics was explained by either pseudo-first order model or Elovich model.

Formation and repair of unavoidable, endogenous interstrand cross-links in cellular DNA.

Genome integrity is essential for life and, as a result, DNA repair systems evolved to remove unavoidable DNA lesions from cellular DNA. Many forms of life possess the capacity to remove interstrand DNA cross-links (ICLs) from their genome but the identity of the naturally-occurring, endogenous substrates that drove the evolution and retention of these DNA repair systems across a wide range of life forms remains uncertain. In this review, we describe more than a dozen chemical processes by which endogenous ICLs plausibly can be introduced into cellular DNA. The majority involve DNA degradation processes that introduce aldehyde residues into the double helix or reactions of DNA with endogenous low molecular weight aldehyde metabolites. A smaller number of the cross-linking processes involve reactions of DNA radicals generated by oxidation.

Targeted deletion of nicotinamide adenine dinucleotide phosphate oxidase 4 from proximal tubules is dispensable for diabetic kidney disease development.

BACKGROUND: The nicotinamide adenine dinucleotide phosphate oxidase isoform 4 (Nox4) mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease (DKD) at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in DKD within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. METHODS: We generated a proximal tubular-specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the sodium-glucose cotransporter-2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. RESULTS: Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of DKD, including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKO STZ mice compared with Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased the mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. CONCLUSIONS: Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence DKD development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes.

Contribution of the Renal Nerves to Hypertension in a Rabbit Model of Chronic Kidney Disease.

Overactivity of the sympathetic nervous system and high blood pressure are implicated in the development and progression of chronic kidney disease (CKD) and independently predict cardiovascular events in end-stage renal disease. To assess the role of renal nerves, we determined whether renal denervation (RDN) altered the hypertension and sympathoexcitation associated with a rabbit model of CKD. The model involves glomerular layer lesioning and uninephrectomy, resulting in renal function reduced by one-third and diuresis. After 3-week CKD, blood pressure was 13±2 mm Hg higher than at baseline (P<0.001), and compared with sham control rabbits, renal sympathetic nerve activity was 1.2±0.5 normalized units greater (P=0.01). The depressor response to ganglion blockade was also +8.0±3 mm Hg greater, but total norepinephrine spillover was 8.7±3.7 ng/min lower (both P<0.05). RDN CKD rabbits only increased blood pressure by 8.0±1.5 mm Hg. Renal sympathetic activity, the response to ganglion blockade and diuresis were similar to sham denervated rabbits (non-CKD). CKD rabbits had intact renal sympathetic baroreflex gain and range, as well as normal sympathetic responses to airjet stress. However, hypoxia-induced sympathoexcitation was reduced by -9±0.4 normalized units. RDN did not alter the sympathetic response to hypoxia or airjet stress. CKD increased oxidative stress markers Nox5 and MCP-1 (monocyte chemoattractant protein-1) in the kidney, but RDN had no effect on these measures. Thus, RDN is an effective treatment for hypertension in this model of CKD without further impairing renal function or altering the normal sympathetic reflex responses to various environmental stimuli.

Differential sympathetic response to lesion-induced chronic kidney disease in rabbits.

Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-ß, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.

Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes.

AIMS/HYPOTHESIS: We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. METHODS: Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. RESULTS: Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (-43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05). CONCLUSIONS/INTERPRETATION: As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion. Graphical abstract.