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Abstract Background It has been proposed that peroxisome proliferator-activated receptor-γ (PPARγ) agonists might reduce renal fibrosis, however, several studies had contradictory results. Moreover, the possible interaction of TGF-β1, PPARγ, and transcription factors in renal fibrosis have not been investigated. We hypothesized that oral pioglitazone treatment would inhibit TGF-β–driven renal fibrosis and its progression, by modulating profibrotic transcription factors in TGF-β1 transgenic mice. Methods Male C57Bl/6 J mice (control, CTL, n = 14) and TGF-β overexpressing transgenic mice (TGFβ, n = 14, having elevated plasma TGF-β1 level) were divided in two sets at 10 weeks of age. Mice in the first set were fed with regular rodent chow (CTL and TGFβ, n = 7/group). Mice in the second set were fed with chow containing pioglitazone (at a dose of 20 mg/kg/day, CTL + Pio and TGFβ+Pio, n = 7/group). After 5 weeks of treatment, blood pressure was assessed and urine samples were collected, and the kidneys were analyzed for histology, mRNA and protein expression. Results TGF-β1 induced glomerulosclerosis and tubulointerstitial damage were significantly reduced by pioglitazone. Pioglitazone inhibited renal mRNA expression of all the profibrotic effectors: type-III collagen, TGF-β1, CTGF and TIMP-1, and alike transcription factors cFos/cJun and protein expression of EGR-1, and STAT3 protein phosphorylation. Conclusions Oral administration of PPARγ agonist pioglitazone significantly reduces TGF-β1-driven renal fibrosis, via the attenuation of EGR-1, STAT3 and AP-1. This implies that PPARγ agonists might be effective in the treatment of chronic kidney disease patients.

Abstract Background Although TGF-ß and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ß and Egr-1 expression. Methods Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. Results Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p

Abstract Background Allopatric speciation has played a particularly important role in archipelagic settings where populations evolve in isolation after colonizing different islands. The Indo-Australasian island realm is an unparalleled natural laboratory of biotic diversification. Here we explore how the level of earth-historic isolation has influenced genetic differentiation across the region by investigating phylogeographic patterns in the Pitta sordida species complex. Results We generated a de novo genome and compared population genomics of 29 individuals of Pitta sordida from the entire distributional range and we reconstructed phylogenetic relationship using mitogenomes, a multi-nuclear gene dataset and single nucleotide polymorphisms (SNPs). We found deep divergence between an eastern and a western group of taxa across Indo-Australasia. Within both groups we have identified major lineages that are geographically separated into Philippines, Borneo, western Sundaland, and New Guinea, respectively. Although these lineages are genetically well-differentiated, suggesting a long-term isolation, there are signatures of extensive gene flow within each lineage throughout the Pleistocene, despite the wide geographic range occupied by some of them. We found little evidence of hybridization or introgression among the studied taxa, but forsteni from Sulawesi makes an exception. This individual, belonging to the eastern clade, is genetically admixed between the western and eastern clades. Geographically this makes sense as Sulawesi is not far from Borneo that houses a population of hooded pittas that belongs to the western clade. Conclusions We found that geological vicariance events cannot explain the current genetic differentiation in the Pitta sordida species complex. Instead, the glacial-interglacial cycles may have played a major role therein. During glacials the sea level could be up to 120 m lower than today and land bridges formed within both the Sunda Shelf and the Sahul Shelf permitting dispersal of floral and faunal elements. The geographic distribution of hooded pittas shows the importance of overwater, “stepping-stone” dispersals not only to deep-sea islands, but also from one shelf to the other. The most parsimonious hypothesis is an Asian ancestral home of the Pitta sordida species complex and a colonization from west to east, probably via Wallacea.