Introduction: Sodium-glucose cotransporter 2 inhibitors such as empagliflozin (EMPA) protect against diabetic kidney disease. Prostaglandin E2 (PGE2) the main renal product of cyclooxygenase-2, inhibits vasopressin (AVP)-water reabsorption in the collecting duct (CD). The novelty of this study is that for the first time, we examined if EMPA affects the renal PGE2/EP receptor system and determined if CD responses to EMPA prevent water loss. Methods: Four groups of adult male mice were studied after 6 weeks of treatment: control (db/m), db/m+EMPA (10 mg/kg/day in chow), type 2 diabetic diabetic/dyslipidemia (db/db), and db/db+EMPA. Tubules were microdissected for quantitative polymerase chain reaction (qPCR) and CD water transport was measured in response to AVP, with or without PGE2. Results: Hyperglycemia and albuminuria were attenuated by EMPA. Renal mRNA expression for COX, PGE synthase, PGE2 (EP) receptor subtypes, CD AVP V2 receptors and aquaporin-2 was elevated in db/db mice, but unchanged by EMPA. Urine PGE2 levels increased in db/db but were unchanged by EMPA. AVP-water reabsorption was comparable in db/m and db/m+EMPA, and equally attenuated to 50% by PGE2. In db/db mice, AVP-water reabsorption was reduced by 50% compared to non-diabetic mice, and this reduction was unaffected by EMPA. In db/db mice, AVP-stimulated water transport was more significantly attenuated with PGE2 (62%), compared to non-diabetic mice, but this attenuation was reduced in response to EMPA, to 28%. Conclusion: In summary, expression of renal PGE2/EP receptors is increased in db/db mice, and this expression is unaffected by EMPA. However, in diabetic CD, PGE2 caused a greater attenuation in AVP-stimulated water reabsorption, and this attenuation is reduced by EMPA. This suggests that EMPA attenuates diabetes-induced excess CD water loss.

Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. To test if combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice, hyperglycemia was induced in genetically hypertensive mice (Lin), followed by HFD regimen. For that, 8-week-old male were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive). LinSTZ were fed a 60% kCal HFD for 8 weeks. Lin mice treated with STZ developed polydipsia, became hypertensive and hyperglycemic. HFD induced weight gain, protected against glomerular hypertrophy, scarring, and albuminuria at endpoint compared to regular diet fed LinSTZ. On the other hand, HFD induced steatosis, liver fibrosis, inflammation, and increase in AST/ALT ratio, characteristics of non-alcoholic liver disease. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS-induced CKD, protected against kidney injury, but inducing liver damage. More studies are necessary to understand the kidney protective mechanisms of HFD when superimposed with hypertension and type 1 diabetes.

Background and Aims Fatty acid receptors have recently been implicated in the progression of fibrotic disorders. GPR40 deletion predisposes to AKI and CKD-induced fibrosis, while deletion of the pro-inflammatory GPR84 receptor was beneficial in this context. PBI-4050, a novel therapeutic compound with excellent safety and efficacy profiles in both experimental and clinical settings, is a dual GPR40 agonist and GPR84 antagonist. In this study, we sought to determine which of these receptors had a predominant effect in adenine-induced CKD. Method Ten-week-old male GPR40/84 double knockout mice (40/84ko) and age/strain matched WT C57BL/6 mice were subjected to a regular or adenine-supplemented diet (0.25%) for 4 weeks (n=10 per group). Plasma samples were collected on a weekly basis for hematocrit assessment. At endpoint, mice were placed in metabolic cages for 24 hours for urine collection. Plasma minerals and electrolytes, urinalysis and a comprehensive blood count were performed at endpoint. Results Adenine feeding led to early and sustained weight-loss, which was significantly worse in WT mice compared to 40/84ko mice. At day 14, Hct was significantly decreased in adenine-fed WT mice, while unaffected in the 40/84ko group. Adenine-induced reductions in hemoglobin and red blood cells counts were also greatly improved in 40/84ko mice. Adenine-feeding led to increased circulating neutrophils and decreased lymphocyte in WT mice, which was not seen in 40/84ko mice. Importantly, renal function assessed by plasma creatinine, urea and creatinine-clearance and renal hypertrophy were significantly improved in Ad-fed 40/84ko mice. Moreover, fractional excretion for sodium, potassium and calcium were increased by adenine-feeding in WT, but not in 40/84ko mice. Conclusion Overall, the loss of both GPR40 and GPR84 led to major improvements in several key renal functional abnormalities associated with adenine-induced CKD including weight-loss, anemia and renal functional decline. These studies, along with our previous work highlight the potential of targeting fatty-acid GPCR’s, notably GPR84, for the treatment of inflammation/fibrosis related kidney diseases.

them for a minimum of one year. Participants were categorised according to whether a change in NT-proBNP levels occurred between baseline and the follow-up visit (Group 1, decrease $10%; Group 2, stable levels; Group 3, increase $10%). The primary outcome was a composite of renal ($40% estimated glomerular filtration rate decline, need for replacement therapy or death from renal causes) and CV (myocardial infarction, hospitalisation for heart failure, stroke or CV death) events, starting from the date of the second NT-proBNP measurement. Cox proportional hazard regressions adjusted for baseline NT-proBNP level were used. Results: We included 127 participants with CKD G4-5 and a median follow-up of 11.1 (IQR 6.8-12.5) months (or 101 patient-years). The median baseline eGFR and NT-proBNP level were 19 (15-23) mL/min/ 1.73m 2 and 1125 (IQR 398-3217) ng/L, respectively. Baseline characteristics were similar across the tree exposure groups. Major adverse events occurred in 20 (51%) of the 39 patients in Group 1 (decreasing levels), 7 (29%) of the 24 in Group 2 (stable levels) and 23 (36%)of the 64 in Group 3 (increasing levels). Compared to patients in Group 2, those in Groups 1 and 3 had similar risks of adverse events [HR 2.02 (95% CI 0.85-4.82), p=0.11 and HR 1.50 (95% CI 0.61-3.69), p=0.38, respectively].Conclusions: In patients with CKD stage G4-5, variability in NT-proBNP levels was not associated with an increased risk of renal or cardiovascular adverse events. albeit this study may not have sufficient power to detect such a difference. Whether NT-proBNP levels monitoring can improve the management of advanced CKD remains to be determined.