Sex-related differences in diabetic kidney disease: A review on the mechanisms and potential therapeutic implications

Piani, Federica; Melena, Isabella; Tommerdahl, Kalie L.; Nokoff, Natalie; Nelson, Robert G.; Pavkov, Meda E.; Raalte, Daniël H. van; Cherney, David Z.I.; Johnson, Richard J.; Nadeau, Kristen J.; Bjornstad, Petter

doi:10.1016/j.jdiacomp.2020.107841

Cited by 37 publications

(50 citation statements)

References 159 publications

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“…Diabetic nephropathy (DN) is a primary cause of endstage renal disease, and it is one of the most common and serious complications of diabetes (Shemesh et al, 2013;Jiang et al, 2017;Wang et al, 2018;Piani et al, 2020). Characteristic lesions of DN include glomerular basement membrane thickening and mesangial extracellular matrix expansion (Kara et al, 2014;Zhang et al, 2015;Dal Monte et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia exacerbates cadmium-induced glomerular nephrosis

Liu

Zhang

2021

Toxicol Ind Health

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Current research suggests that cadmium (Cd) exposure may be associated with the progression of diabetic nephropathy; however, the details of this relationship are insufficiently understood. The present study investigated the effects of elevated glucose on Cd-induced toxicity to glomerular cells using in vitro and in vivo models, and it demonstrated that Cd exposure and the hyperglycemia of diabetes acting together increased the risk of developing glomerular nephrosis . In vitro, human podocytes were exposed to a DMEM low-glucose media without (control), or with Cd (as CdCl2), or a high-glucose media plus Cd. The CCK-8, ROS, apoptosis, and mitochondrial transmembrane potential (ΔΨm) assays showed that human podocytes exposed to Cd in a high-glucose media had greater degrees of injury compared with cells treated with Cd at low (euglycemic)-glucose levels. In vivo, diabetic hyperglycemia was induced by streptozotocin in 8-week-old male C57BL/6 mice to which either CdCl2 or saline (control) was intraperitoneally injected twice weekly for 24 weeks. Compared with euglycemic saline-treated controls, the diabetic mice exposed to Cd demonstrated decreased body weight and increased blood urea nitrogen levels along with histopathological renal architecture changes including collagen fiber accumulation. The results of this study supported the hypothesis that hyperglycemia plus Cd exposure increases the risk of damage to glomerular podocytes compared with Cd exposure in euglycemia.

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Section: Introductionmentioning

confidence: 99%

Hyperglycemia exacerbates cadmium-induced glomerular nephrosis

Liu

Zhang

2021

Toxicol Ind Health

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“…While men had a greater risk of hyperfiltration at time of diabetes diagnosis, women had a greater risk of reduced eGFR. The link between sex and kidney health among adults with type 2 diabetes remains inconclusive ( Maric-Bilkan, 2020 ; Piani et al, 2021 ). Previously observed sex differences have been attributed to differences in hormones and health behaviors ( Piani et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The link between sex and kidney health among adults with type 2 diabetes remains inconclusive ( Maric-Bilkan, 2020 ; Piani et al, 2021 ). Previously observed sex differences have been attributed to differences in hormones and health behaviors ( Piani et al, 2021 ). Differences in kidney outcomes at time of type 2 detection may also indicate differences in duration of type 2 diabetes prior to detection.…”

Section: Discussionmentioning

confidence: 99%

Association of community socioeconomic deprivation with evidence of reduced kidney function at time of type 2 diabetes diagnosis

Hirsch

Nordberg

Chang

et al. 2021

SSM - Population Health

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Background While there are known individual-level risk factors for kidney disease at time of type 2 diabetes diagnosis, little is known regarding the role of community context. We evaluated the association of community socioeconomic deprivation (CSD) and community type with estimated glomerular filtration rate (eGFR) when type 2 diabetes is diagnosed. Methods This was a retrospective cohort study of 13,144 adults with newly diagnosed type 2 diabetes in Pennsylvania. The outcome was the closest eGFR measurement within one year prior to and two weeks after type 2 diabetes diagnosis, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation. We used adjusted multinomial regression models to estimate associations of CSD (quartile 1, least deprivation) and community type (township, borough, city) with eGFR and used adjusted generalized estimating equation models to evaluate whether community features were associated with the absence of diabetes screening in the years prior to type 2 diabetes diagnosis. Results Of the participants, 1279 (9.7%) had hyperfiltration and 1377 (10.5%) had reduced eGFR. Women were less likely to have hyperfiltration and more likely to have reduced eGFR. Black (versus White) race was positively associated with hyperfiltration when the eGFR calculation was corrected for race but inversely associated without the correction. Medical Assistance (ever versus never) was positively associated with reduced eGFR. Higher CSD and living in a city were each positively associated (odds ratio [95% confidence interval]) with reduced eGFR (CSD quartiles 3 and 4 versus quartile 1, 1.23 [1.04, 1.46], 1.32 [1.11, 1.58], respectively; city versus township, 1.38 [1.15, 1.65]). These features were also positively associated with the absence of a type 2 diabetes screening measure. Conclusions In a population-based sample, more than twenty percent had hyperfiltration or reduced eGFR at time of type 2 diabetes diagnosis. Individual- and community-level factors were associated with these outcomes.

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“…Importantly, the cumulative incidence of DKD after 30 years of diabetes is higher in men (4.1%), compared to women (2.5%) 3 . Moreover, diabetic men are at higher risk than diabetic women of progressing to end-stage kidney disease, with hazard ratios ranging from 2.5-3.0 [3][4][5] . Studies involving patients with type 1 or type 2 diabetes and different follow-up times (2.5-18 years) have shown that male sex is significantly associated with the development of microalbuminuria and macroalbuminuria [5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, diabetic men are at higher risk than diabetic women of progressing to end-stage kidney disease, with hazard ratios ranging from 2.5-3.0 [3][4][5] . Studies involving patients with type 1 or type 2 diabetes and different follow-up times (2.5-18 years) have shown that male sex is significantly associated with the development of microalbuminuria and macroalbuminuria [5][6][7][8][9][10] . However, the reasons for the sex-based nature of DKD are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes

Clotet-Freixas

Zaslaver

Pastrello

et al. 2021

Preprint

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Male sex is a risk factor for progression of diabetic kidney disease, but the reasons for this predilection are unclear. Here, we demonstrate that cell sex and sex hormones alter the metabolic phenotype of human proximal tubular epithelial cells (PTECs). Male PTECs displayed increased glycolysis, mitochondrial respiration, oxidative stress, apoptosis, and high glucose-induced injury, compared to female PTECs. This phenotype was enhanced by dihydrotestosterone (DHT) and linked to increased mitochondrial utilization of glucose and glutamine. Studies in vivo pointed towards increased glutamine anaplerosis in diabetic male kidneys. Male sex was linked to increased levels of glutamate, TCA cycle, and glutathione cycle metabolites, in PTECs and in the blood metabolome of healthy youth and youth with type 2 diabetes. Conversely, female PTECs displayed increased levels of pyruvate, glutamyl-cysteine, cysteinylglycine, and a higher GSH/GSSG ratio than male PTECs, indicative of enhanced redox homeostasis. Finally, we identified transcriptional mechanisms that control kidney metabolism in a sex-specific fashion. While X-linked demethylase KDM6A facilitated metabolic homeostasis in female PTECs, transcription factor HNF4A mediated the deleterious effects of DHT in male PTECs. This work uncovers the role of sex in glucose/glutamine metabolism, that may explain the roots of sex dimorphism in the healthy and diabetic kidney.

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Sex-related differences in diabetic kidney disease: A review on the mechanisms and potential therapeutic implications

Cited by 37 publications

References 159 publications

Hyperglycemia exacerbates cadmium-induced glomerular nephrosis

Hyperglycemia exacerbates cadmium-induced glomerular nephrosis

Association of community socioeconomic deprivation with evidence of reduced kidney function at time of type 2 diabetes diagnosis

Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes

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