The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy

Abstract

Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.

Amelioration of Early Markers of Diabetic Nephropathy by Linagliptin in Fructose-Streptozotocin-Induced Type 2 Diabetic Rats

“…Renal cell apoptosis was inhibited by linagliptin as evidenced by mitigation of caspase-7 expression in the kidneys of Fr-STZ rats, a finding that verifies and extends earlier studies that demonstrated the antiapoptotic effects of linagliptin in diabetic rats [65] and in human microvascular endothelial cell cul-ture [45]. The previous findings seem to be consistent with that of Tsuprykov et al [66] who demonstrated that linagliptin ameliorated renal interstitial fibrosis, proteinuria, as well as inflammatory markers via DPP-4-dependent rather than glucose-dependent mechanisms in a non-diabetic rat model for CKD (5/6 nephrectomy). In addition, saxagliptin, another DPP-4 inhibitor inhibited inflammatory and fibrotic related genes and improved urinary albumin excretion independent of its antihyperglycemic effect in a rat model of hypertension-induced renal injury [67], suggesting that DPP-4 inhibitors may exert a renoprotection toward DN progression independent to its glucose lowering properties.…”

“…In addition, this study lacked data on blood pressure, since blood pressure monitoring is a key element in the management of renal complications such as DN together with glycemic control. However, existing studies demonstrated that linagliptin has no modulatory effect on blood pressure in a rat model of non-diabetic CKD [66] and in mice model for DN [52,23].…”

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

“…They suggested a role of DA-1229 in preventing podocyte injury. In non-diabetic rats with 5/6 nephrectomy, linagliptin reduced albuminuria in association with upregulation of downstream targets of atrial natriuretic peptide [31]. Although we failed in reversing heavy proteinuria by using sitagliptin or linagliptin in our rat model of doxorubicin nephropathy, both DPP4 inhibitors were successful in ameliorating tubulointerstitial injury and interstitial fibrosis, most likely via anti-inflammatory action.…”

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

“…DPP-4 inhibitors were found to have renal beneficial effects in animal models of non-diabetic nephropathy such as 5/6 nephrectomy (Tsuprykov et al 2016) Streptozotocin-induced diabetic CD-1 mice Linagliptin -Reduced plasma cystatin C levels and UACR -Ameliorated kidney fibrosis, glomerular size and mesangial area Kanasaki et al (2014), Shi et al (2015) Diabetic db/db mice Gemigliptin -Suppressed albuminuria -Decreased mesangial expansion -Suppressed podocyte apoptosis -Reduced oxidative damage Jung et al (2015), Moon et al (2016) Glp1r 2-kidney-1-clip hypertension (Chaykovska et al 2013), tacrolimus-induced kidney injury (Lim et al 2015), rat Thy-1 glomerulonephritis model (Higashijima et al 2015) and unilateral ureteral obstruction (Min et al 2014).…”