Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression.

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, and the tobacco epidemic exacerbates kidney damage in patients with DN. However, the underlying molecular mechanisms remain unclear. METHOD: In the present study, we used a diabetic mouse model to investigate the molecular mechanisms for nicotine-exacerbated DN. Twelve-week-old female mice were injected with streptozotocin (STZ) to establish a hyperglycemic diabetic model. After four months, the control and hyperglycemic diabetic mice were further divided into four groups (control, nicotine, diabetic mellitus, nicotine + diabetic mellitus) by intraperitoneal injection of nicotine or PBS. After two months, urine and blood were collected for kidney injury assay, and renal tissues were harvested for further molecular assays using RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry. In vitro studies, we used siRNA to suppress Grem1 expression in human podocytes. Then we treated them with nicotine and high glucose to compare podocyte injury. RESULT: Nicotine administration alone did not cause apparent kidney injury, but it significantly increased hyperglycemia-induced albuminuria, BUN, plasma creatinine, and the kidney tissue mRNA expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry analysis revealed that, compared to hyperglycemia or nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and worsened DN. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury. CONCLUSION: Grem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN.

Comprehensive analysis of the gene expression profile of the male and female BTBR mice with diabetic nephropathy.

Comprehensive insight into the gender-based gene expression-related omics data in a rodent model of diabetic nephropathy (DN) is scarce. In the present study, the gender-based genes regulating different pathways involved in the progression of DN were explored through an unbiased RNA sequence of kidneys from BTBR mice with DN. We identified 17,739 and 17,981 genes in male and female DN mice; 1121 and 655 genes were expressed differentially (DEGs, differentially expressed genes) in male and female DN mice; both genders displayed only 195 DEGs. In the male DN mice, the number of upregulated genes was nearly the same as that of the down-regulated genes. In contrast, the number of upregulated genes was lesser than that of the down-regulated genes in the female DN mice, manifesting a remarkable gender disparity during the progression of DN in this animal model. Gene Ontology (GO) and KEGG-enriched results showed that most of these DEGs were related to the critical biological processes, including metabolic pathways, natural oxidation, bile secretion, and PPAR signaling; all are highly associated with DN. Notably, the DEGs significantly enriched for steroid hormone biosynthesis pathway were identified in both genders; the number of DEGs increased was 22 in male DN mice and 14 in female DN mice. Specifically, the Ugt1a10, Akr1c12, and Akr1c14 were upregulated in both genders. Interestingly, the Hsd11b1 gene was upregulated in female DN mice but downregulated in male DN mice. These results suggest that a significant gender-based variance in the gene expression occurs during the progression of DN and may be playing a role in the advancement of DN in the BTBR mouse model.

The Molecular Mechanism of Renal Tubulointerstitial Inflammation Promoting Diabetic Nephropathy.

Diabetic nephropathy (DN) is a common complication affecting many diabetic patients, leading to end-stage renal disease. However, its pathogenesis still needs to be fully understood to enhance the effectiveness of treatment methods. Traditional theories are predominantly centered on glomerular injuries and need more explicit explanations of recent clinical observations suggesting that renal tubules equally contribute to renal function and that tubular lesions are early features of DN, even occurring before glomerular lesions. Although the conventional view is that DN is not an inflammatory disease, recent studies indicate that systemic and local inflammation, including tubulointerstitial inflammation, contributes to the development of DN. In patients with DN, intrinsic tubulointerstitial cells produce many proinflammatory factors, leading to medullary inflammatory cell infiltration and activation of inflammatory cells in the interstitial region. Therefore, understanding the molecular mechanism of renal tubulointerstitial inflammation contributing to DN injury is of great significance and will help further identify key factors regulating renal tubulointerstitial inflammation in the high glucose environment. This will aid in developing new targets for DN diagnosis and treatment and expanding new DN treatment methods.

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways.

The traditional Chinese medicine Gastrodia elata (commonly called "Tianma" in Chinese) has been widely used in the treatment of rheumatism, epilepsy, paralysis, headache, and dizziness. Phenolic compounds, such as gastrodin, para-hydroxybenzyl alcohol (HBA), p-hydroxybenzaldehyde, and vanillin are the main bioactive components isolated from Gastrodia elata. These compounds not only are structurally related but also share similar pharmacological activities, such as antioxidative and anti-inflammatory activities, and effects on the treatment of aging-related diseases. Here, we investigated the effect of para-hydroxybenzyl alcohol (HBA) on neurodegenerative diseases and aging in models of Caenorhabditis elegans (C. elegans). Our results showed that HBA effectively delayed the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease in models of C. elegans. In addition, HBA could increase the average lifespan of N2 worms by more than 25% and significantly improve the age-related physiological functions of worms. Moreover, HBA improved the survival rate of worms under stresses of oxidation, heat, and pathogenic bacteria. Further mechanistic investigation revealed that HBA could activate FOXO/DAF-16 and SKN-1 to regulate antioxidative and xenobiotic metabolism pathway. HBA could also activate HSF-1 to regulate proteostasis maintenance pathway, mitochondrial unfolded stress response, endoplasmic stress response and autophagy pathways. The above results suggest that HBA activated multiple cellular protective pathways to increase stress resistance and protect against aging and aging-related diseases. Overall, our study indicates that HBA is a potential candidate for future development of antiaging pharmaceutical application.