Glomerular mitochondrial changes in HIV associated renal injury

Bryant, Joseph; Guda, Poornachander R.; Asemu, Girma; Subedi, Rogin; Ray, Sugata; Khalid, Omar; Shukla, Vivek; Patel, Dhruvil; Davis, Harry; Nimmagadda, Vamshi K.C.; Makar, Tapas K.

doi:10.1016/j.yexmp.2018.03.004

Cited by 11 publications

(6 citation statements)

References 75 publications

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“…Mitochondrial dysfunction in Tg26 mouse glomeruli and myocytes has been previously reported. 24,56 The present study demonstrated by single-nucleus RNA-seq and Seahorse bioenergetics assay that mitochondrial dysfunction is induced in various cell types in Tg26 kidney, especially proximal tubular cells and endothelial cells. It is likely that HIVAN tubular pathology is mediated, at least in part, by mitochondrial dysfunction in proximal tubular cells, and that glomerular mitochondrial dysfunction is mainly confined to endothelial cells.…”

Section: Discussionmentioning

confidence: 51%

“…Mitochondrial dysfunction in Tg26 mouse kidney and myocytes has been previously reported. 24,50 It is likely that PKR is one of several components that contributes to mitochondrial dysfunction in HIVAN. This warrants the investigation of other causes of mitochondrial dysfunction in HIVAN with the aim to shed further light on injury pathways and to assess feasibility of treatment options.…”

Section: Discussionmentioning

confidence: 99%

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PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy

Yoshida

Latt

Rosenberg

et al. 2022

Preprint

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HIV remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified Stat3 as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high HIV-1 gene expression and dysregulation of cytoskeleton-related genes and these cells dedifferentiated and were lost. Cell-cell interaction analysis suggested that the profibrogenic PKR-STAT3-PDGF-D pathway was activated in injured proximal tubules and was triggered by PDGFRB-expressing fibroblasts throughout the cortex. These findings suggest that PKR inhibition and mitochondrial rescue as potential novel therapeutic approaches for HIVAN.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy

Yoshida

Latt

Rosenberg

et al. 2022

Preprint

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“…Mitochondrial dysfunction and changes in their morphology have been shown to be the cause of HIVAN, which is associated with the expression of viral proteins Nef, Vpr and Tat, ROS generation and apoptosis of renal cells. Tg26 mice kidneys showed significantly lower expression of PGC-1α-promoting mitochondrial biogenesis; mitofusin-2 (MFN2), a mitochondrial membrane protein responsible for mitochondria fusion; and PARKIN-E3 ubiquitin ligase, which induces the autophagic degradation of mitochondria [118,119].…”

Section: Kidney Diseases In Hiv-infected Patients and The Role Of Sirtuinsmentioning

confidence: 99%

Sirtuins as Interesting Players in the Course of HIV Infection and Comorbidities

Jurkowska

Szymańska

Knysz

et al. 2021

Cells

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The sirtuins (SIRTs) are a family of enzymes from the group of NAD+-dependent deacetylases. Through the reaction of splitting the acetyl group of various transcription factors and histones they regulate many processes in the organism. The activity of sirtuins is linked to metabolic control, oxidative stress, inflammation and apoptosis, and they also affect the course of viral infections. For this reason, they may participate in the pathogenesis and development of many diseases, but little is known about their role in the course of human immunodeficiency virus (HIV) infection, which is the subject of this review. In the course of HIV infection, comorbidities such as: neurodegenerative disorders, obesity, insulin resistance and diabetes, lipid disorders and cardiovascular diseases, renal and bone diseases developed more frequently and faster compared to the general population. The role of sirtuins in the development of accompanying diseases in the course of HIV infection may also be interesting. There is still a lack of detailed information on this subject. The role of sirtuins, especially SIRT1, SIRT3, SIRT6, are indicated to be of great importance in the course of HIV infection and the development of the abovementioned comorbidities.

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“…In 2020, an estimated 37.7 million people were living with the human immunodeficiency virus (HIV) worldwide, of which 1.7 million were younger than 15 years of age [ 1 , 2 ]. HIV infection has been associated with impaired kidney function in adults and children [ 3 , 4 , 5 ]. Generally, kidney impairment results from HIV-associated nephropathy, HIV-associated immune complex kidney disease, viral co-infections, or kidney damage induced by antiretroviral drugs [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling

et al. 2023

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Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine and emtricitabine compound models in Simcyp® (v21) were verified in adult populations with and without CKD and in non-CKD paediatric populations. We developed paediatric CKD population models reflecting subjects with a reduced glomerular filtration and tubular secretion, based on extrapolation from adult CKD population models. These models were verified using ganciclovir as a surrogate compound. Then, lamivudine and emtricitabine dosing strategies were simulated in virtual paediatric CKD populations. The compound and paediatric CKD population models were verified successfully (prediction error within 0.5- to 2-fold). The mean AUC ratios in children (GFR-adjusted dose in CKD population/standard dose in population with normal kidney function) were 1.15 and 1.23 for lamivudine, and 1.20 and 1.30 for emtricitabine, with grade-3- and -4-stage CKD, respectively. With the developed paediatric CKD population PBPK models, GFR-adjusted lamivudine and emtricitabine dosages in children with CKD resulted in adequate drug exposure, supporting paediatric GFR-adjusted dosing. Clinical studies are needed to confirm these findings.

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Glomerular mitochondrial changes in HIV associated renal injury

Cited by 11 publications

References 75 publications

PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy

PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy

Sirtuins as Interesting Players in the Course of HIV Infection and Comorbidities

Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling

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