The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor‐neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin–angiotensin system inhibitors (RAS‐Is) in large clinical trials such as the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI [Angiotensin‐Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS‐Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM‐HF trial, ARNI was associated with more albuminuria compared with RAS‐I; thus, it is unclear whether long‐term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS‐I in patients with chronic kidney disease in the UK HARP‐III (United Kingdom Heart and Renal Protection‐III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS‐I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

Aims Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium‐glucose cotransporter 2 inhibitors (SGLT2‐Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta‐analysis to investigate the effects of SGLT2‐Is, MRAs and their combination on albuminuria in type 2 DM. Methods We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2‐Is, MRAs + SGLT2‐Is, or a placebo in patients with type 2 DM with a urinary albumin‐creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. Results This meta‐analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2‐Is and MRAs was associated with lower albuminuria compared with the use of SGLT2‐Is, MRAs, or the placebo alone [mean difference (95% CI): −34.19 (−27.30; −41.08), −32.25 (−24.53; −39.97) and −65.22 (−57.97; −72.47), respectively]. Treatment with SGLT2‐Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): −31.03 (−28.35; −33.72) and −32.97 (−29.68; −36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2‐Is. Sensitivity analyses showed similar results. Conclusion Combination therapy with SGLT2‐Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2‐Is or MRAs alone.

Objective:We previously reported that genetic knockdown of angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) exacerbated the aging-associated kidney tubulointerstitial fibrosis in mice (Uneda K, et al. J Am Heart Assoc 2017). However, little is known about whether enhancement of ATRAP expression could affect any pathological stimuli-induced kidney fibrosis and inflammation. Recently we proposed that aristolochic acid nephropathy (AAN) might be a useful model of kidney aging along with tubulointerstitial fibrosis (Urate S, et al. Int J Mol Sci 2021). The present study was designed to investigate the functional role of ATRAP in kidney fibrosis and inflammation, using ATRAP transgenic mice subjected to AAN.Design and method:We generated ATRAP transgenic (Tg19) mice under the control of chicken β;-actin promoter. (Wakui H, et al. Am J Physiol Renal Physiol 2010). The level of kidney ATRAP protein expression was about 4-fold higher in the Tg19 mice compared with wild-type littermate control (LC) mice. The Tg19 mice and LC mice were administered either vehicle or aristolochic acid (AA) (3 mg/kg) for 4 weeks, followed by a 4-week remodeling period. Kidney fibrosis was examined by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with inflammation, fibrosis, and senescence were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immuno blot analyses.Results:AA administration provoked kidney fibrosis and inflammation accompanied by decreased kidney function. There were no significant differences in AA-induced kidney fibrosis estimated by qRT-PCR and histological analysis between the Tg19 and LC mice. Creatinine clearance was similarly decreased in the Tg19 and LC mice with AAN. However, AA-induced macrophage infiltration was significantly suppressed in the kidney of Tg19 mice compared with that of the LC mice. In addition, inflammation-, aging-, and oxidative stress-related genes (tumor necrosis factor-α, interleukin-1β;, cyclin-dependent kinase inhibitor 2A, wnt family member 9A, nicotinamide adenine dinucleotide phosphate oxidase 2) in response to AA administration were significantly suppressed in the kidney of the Tg19 mice compared with that of the LC mice.Conclusion:These results indicate that the enhancement of ATRAP expression suppresses kidney inflammation despite no evident effects on kidney fibrosis in a mouse model of AAN. ATRAP may be a therapeutic target for inflammation associated with CKD.

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Objective:Angiotensin receptor-neprilysin inhibitors (ARNI) are potential therapeutic candidates for the treatment of cardiorenal syndrome. Although evidence is accumulating on the therapeutic effects of ARNI for heart failure and hypertension, the effects of ARNI on kidney disease or cardiorenal syndrome are controversial. To address this issue, we investigated the organ-protective effect of ARNI on cardiorenal syndrome using the ANS [Ang II (A) + nephrectomy (N) + saline (S)] mice, which is the cardiorenal syndrome model.Design and method:C57BL/6 mice were divided into 5 groups: Control (sham operation) group, ANS (ANS + vehicle treatment) group, Val M [ANS + moderate dose of valsartan treatment (30 mg/kg/day)] group, ARNI [ANS + sacubitril/valsartan treatment (60 mg/kg/day)] group, and Val H [ANS + high dose of valsartan treatment (60 mg/kg/day)] group. Sacrifice was performed after 4 weeks, and various analyses were conducted.Results:ARNI, Val M, and Val H treatment groups attenuated the elevation of blood pressure in ANS mice; valsartan exerted its antihypertensive effect in a dose-dependent manner, and the antihypertensive effect of the ARNI group was intermediate between Val M and Val H groups. Regardless of the strength of the antihypertensive effect, the ARNI group was most effective in preventing the decrease in cardiac contraction and cardiac fibrosis in ANS mice. However, the ARNI group was insufficient to suppress urinary albumin excretion and renal fibrosis in ANS mice. Both valsartan groups suppressed urinary albumin excretion in ANS mice, as well as renal fibrosis and glomerular swelling. In addition, RNA sequencing analysis suggested that ARNI and valsartan may involve different molecular mechanisms in the kidney.Conclusions:The ARNI group showed better cardioprotective effects than both of valsartan treatment groups, but not sufficient kidney protection. These results of present study using a mouse model of cardiorenal syndrome suggested that the relationship between the antihypertensive effects and the organ protective effects of cardiorenal injury may be different between angiotensin II receptor blocker (ARB) and ARNI.