Rosiglitazone Treatment Attenuates Expression of Inflammatory Hallmarks in the Remaining Kidney following Contralateral Nephrectomy

Abstract

Background/Aims: Following kidney donation, living kidney donors have been reported to develop anemia and pronounced inflammation. Therapeutic strategies for ameliorating unilateral nephrectomy-induced inflammation would be beneficiary for the living donors. We applied rosiglitazone to attenuate inflammatory processes ongoing within the remaining kidney following contralateral nephrectomy. Methods: 20 Sprague-Dawley rats were subjected to left unilateral nephrectomy and 20 others to sham operation. Half of each group was treated for 2 weeks with rosiglitazone (5 mg/kg body weight). After sacrifice, intrarenal transforming growth factor (TGF)-β, angiotensin-II (A-II), interleukin (IL)-6, IL-10, IL-4 and nitric oxide (NO) were assessed, and histologic sections stained to assess the inflammatory cell infiltration. Renal function was evaluated by creatinine, urea, cystatin C measurements. Results: Intrarenal IL-6, A-II and TGF-β were significantly augmented, while NO was significantly decreased in kidneys remaining after contralateral nephrectomy. Rosiglitazone treatment abrogated augmented IL-6, A-II and TGF-β synthesis and restored intrarenal NO availability in the remaining kidneys. Rosiglitazone also augmented anti-inflammatory IL-4 cytokine synthesis, while IL-10 production, leukocyte infiltration and renal function parameters remained unchanged. Conclusions: Rosiglitazone treatment attenuates the proinflammatory responses, repre- sented by augmented IL-6, A-II and TGF-β production, developing in the remaining kidney following contralateral nephrectomy. In addition, by stimulating IL-4 synthesis and restoring NO availability, rosiglitazone treatment initiates counteractive anti-inflammatory responses in the remaining kidney.

Rosiglitazone treatment attenuates renal tissue inflammation generated by urinary tract obstruction

“…Rosiglitazone treatment also abrogated the outburst of IL‐6 synthesis in ligated kidney tissues at any experimental time point. Profound elevation of IL‐6 was evident up to 24 h. Renal ablation has been previously shown to trigger augmented IL‐6 as well as a variety of other pro‐ and anti‐inflammatory processes in the remaining kidneys 24,25 . IL‐6 has been previously demonstrated to be actively involved in development of fibrosis in patients with systemic sclerotic disease 26 .…”

“…Interleukin-6 synthesis was significantly augmented in cortices from the ligated kidneys 1 h and 24 h after obstruction (1650. 25 1 264.98 pg/ mL, P < 0.001). Following 2 weeks, IL-6 production in medullae, similarly to cortices, decreased to the levels close to sham-operated controls (Fig.…”

Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes

“…SBP was monitored every 2 weeks from 10 to 14 weeks of age. At 12 weeks of age, 14 of the diabetic SHRs were treated with RGZ (5 mg/kg of body weight; GlaxoSmithKline) [18], and SHRs, diabetic SHRs and WKY rats were treated daily with a placebo by oral gavage for 2 weeks. Rats were killed at 14 weeks old.…”

Angiotensin-(1–7) prevents diabetes-induced attenuation in PPAR-γ and catalase activities

“…Activation of PPAR-γ has been reported as the target of several therapeutic agents including thiazolidinediones (or glitazones) that are used in the treatment of diabetes (Etgen and Mantlo 2003; Fogo 2008; Gervois et al, 2004). Activators of PPAR-γ such as glitazones that were originally established as insulin sensitizers, are now known to reduce hypertension, Ang II-induced oxidative stress, production of inflammatory markers such as NF-kB and improve dyslipidemia in patients with type II diabetes (Fogo et al, 2008; Duan et al, 2008; Efrati et al, 2008; Yousefipour et al, 2007, Touyz and Schiffrin, 2006). Moreover, angiotensin converting enzyme (ACE) inhibitors and angiotensin type-1 (AT 1 ) receptor blockers especially telmisartan (and to a lesser degree candesartan and irbesartan) have been reported to partially increase PPAR- activity (Erbe et al, 2006; Fogo et al, 2008; Kurtz 2008; Kurtz and Pravenee, 2004; Unger and Stoppelhaar, 2007; Yamagishi et al, 2008).…”