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Continuous feeding of high dietary sugar is strongly associated with type 2 diabetes (T2D) and its secondary complications. Diabetic nephropathy (DN) is a major secondary complication that leads to glomerular and renal tubular dysfunction. The present study is aimed to investigate the effects of chronic exposure of high sugar diet (HSD) on renal tubules. Malpighian tubules (MTs), a renal organ of Drosophila, were used as a model in the study. Feeding of HSD develops T2D condition in Drosophila. The MTs showed structural abnormalities in 20 days of HSD fed flies. Impaired insulin signaling, oxidative stress, enhanced levels of AGE-RAGE and induction of apoptosis were observed in the MTs of these flies. Further, altered expression of transporters, enhanced uric acid level and reduced fluid secretion rate confirmed the impaired function of MTs in these flies. RNA-seq and RT-PCR analyses in the MTs of HSD fed-and control-flies revealed the altered expression of candidate genes that regulate several important pathways including extracellular matrix (ECM), advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE), transforming growth factor β (TGF-β), galactose, starch and sucrose metabolism that are well known mediators of renal tubular dysfunction in DN patients. Disruption of insulin signaling in the MTs also causes renal tubular dysfunction similar to HSD fed flies. Overall, the study suggests that phenotypes observed in the MTs of HSD fed flies recapitulate several hallmarks of renal tubular dysfunction in DN patients. Therefore, we conclude that MTs of HSD fed flies may be used for deciphering the underlying mechanisms of T2D mediated renal tubular dysfunction., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Xenobiotic mediated renal toxicity is one of the major health concerns to the organisms, including humans. New chemicals with nephrotoxic potential are continuously being added to the list of existing nephrotoxicants. To predict the nephrotoxicity of these new chemicals, reliable and cost-effective alternative animal models are required. It is a prerequisite for the identification and assessment of these compounds as potential nephrotoxicants to prevent renal toxicity in the exposed population. Drosophila melanogaster, a genetically tractable invertebrate animal model, has a renal system functionally analogous to humans. The Malpighian tubules (MTs) of D. melanogaster are similar to the tubular part of nephron of the human kidney. Besides, it recapitulates the renal toxicity hallmark with mammals when exposed to known nephrotoxicants. In this study, first instar larvae of D. melanogaster (Oregon R) were exposed to different concentrations of two well-known nephrotoxicants, cadmium (Cd) and mercury (Hg). Akin to higher organisms, Cd and Hg exposure to D. melanogaster produce similar phenotypes. MTs of exposed D. melanogaster larvae exhibited increased oxidative stress, activated cellular antioxidant defense mechanism, GSH depletion, increased cleaved caspase-3 expression, increased DEVDase activity and increased cell death. The functional status of MTs was assessed by fluid secretion rate (FSR), efflux activity of transporter protein, mitochondrial membrane potential (MMP), ATP level and expression of junctional protein (Dlg). All the phenotypes observed in MTs of D. melanogaster larvae recapitulate the phenotypes observed in higher organisms. Increased uric acid level, the hallmark of renal dysfunction, was also observed in exposed larvae. Taken together, the study suggests that MTs of D. melanogaster may be used as a functional model to evaluate xenobiotic mediated nephrotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cadmium (Cd) exposure to the animals including humans is reported as nephrotoxic compounds i.e. , disturbing redox status (increase oxidative stress), mitochondrial dysfunction, renal cell death and altered transporters in the renal system. Hsp27 (a small heat shock protein) has been shown as one of the modulators in the renal dysfunction and increased against the Cd induced toxicity. However, no studies are reported on the genetic modulation of stress protein against the Cd-induced nephrotoxicity. The current study aimed to examine the protective role of hsp27 overexpression against the Cd-induced nephrotoxicity using Drosophila melanogaster as an animal model. D. melanogaster renal system includes nephrocytes and Malpighian tubules (MTs) that show the functional similarity with mammalian kidney nephron. Overexpression of the hsp27 was found to reduce the Cd induced oxidative stress, rescue cell death in MTs of Cd exposed D. melanogaster larvae. The rescued GSH level, NADPH level and glucose 6 phosphate dehydrogenase (G6PD) activity were also observed in the MTs of the Cd exposed organism. Function (efflux activity and fluid secretion rate) of the MTs was restored in Cd exposed hsp27 overexpressed larvae. Further, results were confirmed by restored brush border microvilli density and reduced uric acid level. Tissue specific knockdown of hsp27 developed Cd like phenotypes in MTs and the phenotypes enhanced in Cd exposed condition. The present study clearly shows the role of hsp27 overexpression in restoration of the MTs function and protection against the Cd induced renal toxicity. [Display omitted] • This study first time report nephroprotective role of hsp27 in Cd induce renal toxicity in MTs of the D. melanogaster larvae. • This study first time report nephroprotective role of hsp27 in Cd induce renal toxicity in MTs of the D. melanogaster larvae. • hsp27 overexpression restores MMP, ATP level and microvilli brush border density in MTs of Cd exposed D. melanogaster larvae. • hsp27 knockdown negatively alter MTs functions in D. melanogaster larvae and more severely affect after the Cd exposure. [ABSTRACT FROM AUTHOR]