Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.

Lessons learned from an enterprise-wide clinical datathon.

In 2020, Baylor College of Medicine held a datathon to inform potential users of a new data warehouse, allow users to address clinical questions, identify warehouse capabilities and limitations, foster collaborations, and engage trainees. Senior faculty selected proposals based on feasibility and impact. Selectees worked with Information Technology for 2 months and presented findings. A survey of participants showed diverse levels of experience, high perceived value of the datathon, high rates of collaboration, and significant increases in knowledge. A datathon can promote familiarity with a new data warehouse, guide data warehouse improvement, and promote collaboration.

Smoking Status and Factors associated with COVID-19 In-Hospital Mortality among US Veterans.

INTRODUCTION: The role of smoking in risk of death among patients with COVID-19 remains unclear. We examined the association between in-hospital mortality from COVID-19 and smoking status and other factors in the United States Veterans Health Administration (VHA). METHODS: This is an observational, retrospective cohort study using the VHA COVID-19 shared data resources for February 1 to September 11, 2020. Veterans admitted to the hospital who tested positive for SARS-CoV-2 and hospitalized by VHA were grouped into Never (as reference, NS), Former (FS), and Current smokers (CS). The main outcome was in-hospital mortality. Control factors were the most important variables (among all available) determined through a cascade of machine learning. We reported adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) from logistic regression models, imputing missing smoking status in our primary analysis. RESULTS: Out of 8 667 996 VHA enrollees, 505 143 were tested for SARS-CoV-2 (NS = 191 143; FS = 240 336; CS = 117 706; Unknown = 45 533). The aOR of in-hospital mortality was 1.16 (95%CI 1.01, 1.32) for FS vs. NS and 0.97 (95%CI 0.78, 1.22; p > .05) for CS vs. NS with imputed smoking status. Among other factors, famotidine and nonsteroidal anti-inflammatory drugs (NSAID) use before hospitalization were associated with lower risk while diabetes with complications, kidney disease, obesity, and advanced age were associated with higher risk of in-hospital mortality. CONCLUSIONS: In patients admitted to the hospital with SARS-CoV-2 infection, our data demonstrate that FS are at higher risk of in-hospital mortality than NS. However, this pattern was not seen among CS highlighting the need for more granular analysis with high-quality smoking status data to further clarify our understanding of smoking risk and COVID-19-related mortality. Presence of comorbidities and advanced age were also associated with increased risk of in-hospital mortality. IMPLICATIONS: Veterans who were former smokers were at higher risk of in-hospital mortality compared to never smokers. Current smokers and never smokers were at similar risk of in-hospital mortality. The use of famotidine and nonsteroidal anti-inflammatory drugs (NSAIDs) before hospitalization were associated with lower risk while uncontrolled diabetes mellitus, advanced age, kidney disease, and obesity were associated with higher risk of in-hospital mortality.

Role of SIRT1 in HIV-associated kidney disease.

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes.

The pathophysiology of human immunodeficiency virus (HIV)-associated cardiomyopathy remains uncertain. We used HIV-1 transgenic (Tg26) mice to explore mechanisms by which HIV-related proteins impacted on myocyte function. Compared to adult ventricular myocytes isolated from nontransgenic (wild type [WT]) littermates, Tg26 myocytes had similar mitochondrial membrane potential (ΔΨ m ) under normoxic conditions but lower Δ Ψ m after hypoxia/reoxygenation (H/R). In addition, Δ Ψ m in Tg26 myocytes failed to recover after Ca 2+ challenge. Functionally, mitochondrial Ca 2+ uptake was severely impaired in Tg26 myocytes. Basal and maximal oxygen consumption rates (OCR) were lower in normoxic Tg26 myocytes, and further reduced after H/R. Complex I subunit and ATP levels were lower in Tg26 hearts. Post-H/R, mitochondrial superoxide (O 2•- ) levels were higher in Tg26 compared to WT myocytes. Overexpression of B-cell lymphoma 2-associated athanogene 3 (BAG3) reduced O 2•- levels in hypoxic WT and Tg26 myocytes back to normal. Under normoxic conditions, single myocyte contraction dynamics were similar between WT and Tg26 myocytes. Post-H/R and in the presence of isoproterenol, myocyte contraction amplitudes were lower in Tg26 myocytes. BAG3 overexpression restored Tg26 myocyte contraction amplitudes to those measured in WT myocytes post-H/R. Coimmunoprecipitation experiments demonstrated physical association of BAG3 and the HIV protein Tat. We conclude: (a) Under basal conditions, mitochondrial Ca 2+ uptake, OCR, and ATP levels were lower in Tg26 myocytes; (b) post-H/R, Δ Ψ m was lower, mitochondrial O 2•- levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; and (c) BAG3 overexpression decreased O 2•- levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol.

Epigenetic regulation of RCAN1 expression in kidney disease and its role in podocyte injury.

Mounting evidence suggests that epigenetic modification is important in kidney disease pathogenesis. To determine whether epigenetic regulation is involved in HIV-induced kidney injury, we performed genome-wide methylation profiling and transcriptomic profiling of human primary podocytes infected with HIV-1. Comparison of DNA methylation and RNA sequencing profiles identified several genes that were hypomethylated with corresponding upregulated RNA expression in HIV-infected podocytes. Notably, we found only one hypermethylated gene with corresponding downregulated RNA expression, namely regulator of calcineurin 1 (RCAN1). Further, we found that RCAN1 RNA expression was suppressed in glomeruli in human diabetic nephropathy, IgA nephropathy, and lupus nephritis, and in mouse models of HIV-associated nephropathy and diabetic nephropathy. We confirmed that HIV infection or high glucose conditions suppressed RCAN1 expression in cultured podocytes. This suppression was alleviated upon pretreatment with DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine, suggesting that RCAN1 expression is epigenetically suppressed in the context of HIV infection and diabetic conditions. Mechanistically, increased expression of RCAN1 decreased HIV- or high glucose-induced nuclear factor of activated T cells (NFAT) transcriptional activity. Increased RCAN1 expression also stabilized actin cytoskeleton organization, consistent with the inhibition of the calcineurin pathway. In vivo, knockout of RCAN1 aggravated albuminuria and podocyte injury in mice with Adriamycin-induced nephropathy. Our findings suggest that epigenetic suppression of RCAN1 aggravates podocyte injury in the setting of HIV infection and diabetic nephropathy.

Cardiac Dysfunction in HIV-1 Transgenic Mouse: Role of Stress and BAG3.

Since highly active antiretroviral therapy improved long-term survival of acquired immunodeficiency syndrome (AIDS) patients, AIDS cardiomyopathy has become an increasingly relevant clinical problem. We used human immunodeficiency virus (HIV)-1 transgenic (Tg26) mouse to explore molecular mechanisms of AIDS cardiomyopathy. Tg26 mice had significantly lower left ventricular (LV) mass and smaller end-diastolic and end-systolic LV volumes. Under basal conditions, cardiac contractility and relaxation and single myocyte contraction dynamics were not different between wild-type (WT) and Tg26 mice. Ten days after open heart surgery, contractility and relaxation remained significantly depressed in Tg26 hearts, suggesting that Tg26 mice did not tolerate surgical stress well. To simulate heart failure in which expression of Bcl2-associated athanogene 3 (BAG3) is reduced, we down-regulated BAG3 by small hairpin ribonucleic acid in WT and Tg26 hearts. BAG3 down-regulation significantly reduced contractility in Tg26 hearts. BAG3 overexpression rescued contractile abnormalities in myocytes expressing the HIV-1 protein Tat. We conclude: (i) Tg26 mice exhibit normal contractile function at baseline; (ii) Tg26 mice do not tolerate surgical stress well; (iii) BAG3 down-regulation exacerbated cardiac dysfunction in Tg26 mice; (iv) BAG3 overexpression rescued contractile abnormalities in myocytes expressing HIV-1 protein Tat; and (v) BAG3 may occupy a role in pathogenesis of AIDS cardiomyopathy.

Trends in the outcomes of end-stage renal disease secondary to human immunodeficiency virus-associated nephropathy.

BACKGROUND: Little is known about the trends in the incidence and outcomes of patients with end-stage renal disease (ESRD) attributed to human immunodeficiency virus-associated nephropathy (HIVAN). We sought to define relative incidence among ESRD patients, changes in mortality among patients with ESRD attributed to HIVAN, as well as changes in the excess mortality experienced by patients with ESRD attributed to HIVAN compared with otherwise similar ESRD patients with non-HIVAN causes. METHODS: We used the US Renal Data System to identify all individuals with reported HIVAN who initiated treatment for ESRD between 1989 and 2011. We plotted their counts and proportions among all incident ESRD patients and tabulated their characteristics across years. We then compared mortality within the HIVAN group across years using Cox regression. In addition, we studied the trends in relative mortality of HIVAN patients versus those with ESRD not reported as HIVAN. RESULTS: Overall, 14 719 individuals with HIVAN-ESRD were recorded, with significant reductions in recent years (893 in 2006; 525 in 2011). Compared with patients initiating dialysis between 1989 and 1992, mortality declined by 40% (HR = 0.60; 95% CI, 0.55-0.65) and 64% (HR = 0.36; 95% CI, 0.32-0.40) for patients initiating dialysis in 1999/2000 and 2009-11, respectively. The adjusted excess mortality of HIVAN-ESRD patients versus incident ESRD patients from other causes was >5-fold in 1989-92 (HR = 5.21; 95% CI, 4.84-5.60); this excess mortality has subsequently declined but remained at almost 3-fold in recent years (e.g. HR = 2.58; 95% CI, 2.37-2.80, 2009-11 incidence cohort). CONCLUSIONS: Concurrent with the increasing availability of highly active antiretroviral therapy (HAART), both the incidence of ESRD due to HIVAN and the mortality of such patients have decreased substantially. However, HIVAN patients reaching ESRD continue to experience substantial excess mortality compared with other ESRD patients even in the current era of modern HAART.

Proteomics analysis of the non-muscle myosin heavy chain IIa-enriched actin-myosin complex reveals multiple functions within the podocyte.

MYH9 encodes non-muscle myosin heavy chain IIA (NMMHCIIA), the predominant force-generating ATPase in non-muscle cells. Several lines of evidence implicate a role for MYH9 in podocytopathies. However, NMMHCIIA's function in podocytes remains unknown. To better understand this function, we performed immuno-precipitation followed by mass-spectrometry proteomics to identify proteins interacting with the NMMHCIIA-enriched actin-myosin complexes. Computational analyses revealed that these proteins belong to functional networks including regulators of cytoskeletal organization, metabolism and networks regulated by the HIV-1 gene nef. We further characterized the subcellular localization of NMMHCIIA within podocytes in vivo, and found it to be present within the podocyte major foot processes. Finally, we tested the effect of loss of MYH9 expression in podocytes in vitro, and found that it was necessary for cytoskeletal organization. Our results provide the first survey of NMMHCIIA-enriched actin-myosin-interacting proteins within the podocyte, demonstrating the important role of NMMHCIIA in organizing the elaborate cytoskeleton structure of podocytes. Our characterization of NMMHCIIA's functions goes beyond the podocyte, providing important insights into its general molecular role.

Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis-associated glomerular injury.

Injury to the specialized epithelial cells of the glomerulus (podocytes) underlies the pathogenesis of all forms of proteinuric kidney disease; however, the specific genetic changes that mediate podocyte dysfunction after injury are not fully understood. Here, we performed a large-scale insertional mutagenic screen of injury-resistant podocytes isolated from mice and found that increased expression of the gene Rap1gap, encoding a RAP1 activation inhibitor, ameliorated podocyte injury resistance. Furthermore, injured podocytes in murine models of disease and kidney biopsies from glomerulosclerosis patients exhibited increased RAP1GAP, resulting in diminished glomerular RAP1 activation. In mouse models, podocyte-specific inactivation of Rap1a and Rap1b induced massive glomerulosclerosis and premature death. Podocyte-specific Rap1a and Rap1b haploinsufficiency also resulted in severe podocyte damage, including features of podocyte detachment. Over-expression of RAP1GAP in cultured podocytes induced loss of activated ß1 integrin, which was similarly observed in kidney biopsies from patients. Furthermore, preventing elevation of RAP1GAP levels in injured podocytes maintained ß1 integrin-mediated adhesion and prevented cellular detachment. Taken together, our findings suggest that increased podocyte expression of RAP1GAP contributes directly to podocyte dysfunction by a mechanism that involves loss of RAP1-mediated activation of ß1 integrin.

Novel small leucine-rich repeat protein podocan is a negative regulator of migration and proliferation of smooth muscle cells, modulates neointima formation, and is expressed in human atheroma.

BACKGROUND: Smooth muscle cell (SMC) migration and proliferation critically influence the clinical course of vascular disease. We tested the effect of the novel small leucine-rich repeat protein podocan on SMC migration and proliferation using a podocan-deficient mouse in combination with a model of arterial injury and aortic explant SMC culture. In addition, we examined the effect of overexpression of the human form of podocan on human SMCs and tested for podocan expression in human atherosclerosis. In all these conditions, we concomitantly evaluated the Wnt-TCF (T-cell factor) pathway. METHODS AND RESULTS: Podocan was strongly and selectively expressed in arteries of wild-type mice after injury. Podocan-deficient mice showed increased arterial lesion formation compared with wild-type littermates in response to injury (P<0.05). Also, SMC proliferation was increased in arteries of podocan-deficient mice compared with wild-type (P<0.05). In vitro, migration and proliferation were increased in podocan-deficient SMCs and were normalized by transfection with the wild-type podocan gene (P<0.05). In addition, upregulation of the Wnt-TCF pathway was found in SMCs of podocan-deficient mice both in vitro and in vivo. On the other hand, podocan overexpression in human SMCs significantly reduced SMC migration and proliferation, inhibiting the Wnt-TCF pathway. Podocan and a Wnt-TCF pathway marker were differently expressed in human coronary restenotic versus primary lesions. CONCLUSIONS: Podocan appears to be a potent negative regulator of the migration and proliferation of both murine and human SMCs. The lack of podocan results in excessive arterial repair and prolonged SMC proliferation, which likely is mediated by the Wnt-TCF pathway.

Estimating kidney function in HIV-infected adults in Kenya: comparison to a direct measure of glomerular filtration rate by iohexol clearance.

BACKGROUND: More than two-thirds of the world's HIV-positive individuals live in sub-Saharan Africa, where genetic susceptibility to kidney disease is high and resources for kidney disease screening and antiretroviral therapy (ART) toxicity monitoring are limited. Equations to estimate glomerular filtration rate (GFR) from serum creatinine were derived in Western populations and may be less accurate in this population. METHODS: We compared results from published GFR estimating equations with a direct measure of GFR by iohexol clearance in 99 HIV-infected, ART-naïve Kenyan adults. Iohexol concentration was measured from dried blood spots on filter paper. The bias ratio (mean of the ratio of estimated to measured GFR) and accuracy (percentage of estimates within 30% of the measured GFR) were calculated. RESULTS: The median age was 35 years, and 60% were women. The majority had asymptomatic HIV, with median CD4+ cell count of 355 cells/mm(3). Median measured GFR was 115 mL/min/1.73 m(2). Overall accuracy was highest for the Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation. Consistent with a prior report, bias and accuracy were improved by eliminating the coefficient for black race (85% of estimates within 30% of measured GFR). Accuracy of all equations was poor in participants with GFR 60-90 mL/min/1.73 m(2) (<65% of estimates within 30% of measured GFR), although this subgroup was too small to reach definitive conclusions. CONCLUSIONS: Overall accuracy was highest for the CKD-EPI equation. Eliminating the coefficient for race further improved performance. Future studies are needed to determine the most accurate GFR estimate for use in individuals with GFR <90 mL/min/1.73 m(2), in whom accurate estimation of kidney function is important to guide drug dosing. Direct measurement of GFR by iohexol clearance using a filter paper based assay is feasible for research purposes in resource-limited settings, and could be used to develop more accurate GFR estimates in African populations.

Renoprotective effect of combined inhibition of angiotensin-converting enzyme and histone deacetylase.

The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases. In addition, this study provides proof-of-concept that drug-induced expression signatures have potential use in predicting the effects of combination drug therapy.

Inhibition of Notch pathway attenuates the progression of human immunodeficiency virus-associated nephropathy.

The Notch pathway is an evolutionarily conserved signaling cascade that is critical in kidney development and has also been shown to play a pathogenetic role in a variety of kidney diseases. We have previously shown that the Notch signaling pathway is activated in human immunodeficiency virus-associated nephropathy (HIVAN) as well as in a rat model of the disease. In this study, we examined Notch signaling in the well established Tg26 mouse model of HIVAN. Notch signaling components were distinctly upregulated in the kidneys of these mice as well as in immortalized podocytes derived from these mice. Notch1 and Notch4 were upregulated in the Tg26 glomeruli, and Notch4 was also expressed in tubules. Notch ligands Jagged1, Jagged2, Delta-like1, and Delta-like 4 were all upregulated in the tubules of Tg26 mice, but glomeruli showed minimal expression of Notch ligands. To examine a potential pathogenetic role for Notch in HIVAN, Tg26 mice were treated with GSIXX, a gamma secretase inhibitor that blocks Notch signaling. Strikingly, GSIXX treatment resulted in significant improvement in both histological kidney injury scores and renal function. GSIXX-treated Tg26 mice also showed diminished podocyte proliferation and dedifferentiation, cellular hallmarks of the disease. Moreover, GSIXX blocked podocyte proliferation in vitro induced by HIV proteins Nef and Tat. These studies suggest that Notch signaling can promote HIVAN progression and that Notch inhibition may be a viable treatment strategy for HIVAN.

Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy.

OBJECTIVE: HIV-1 gene expression in kidney epithelial cells is thought to be responsible for the pathogenesis of HIV-1-associated nephropathy (HIVAN). Signal transducer and activator of transcription (STAT) 3 signaling is activated in podocytes of patients with HIVAN and drives the dedifferentiation and proliferation of podocytes in culture. We confirm here that deletion of podocyte STAT3 is sufficient to mitigate the glomerular as well as tubulointerstitial findings of HIVAN. METHODS: To demonstrate the functional role of podocyte STAT3 in the pathogenesis of HIVAN we compared the development of HIVAN in Tg26 HIV-transgenic mice with and without deletion of STAT3 in the podocyte. RESULTS: Tg26 mice with podocyte-specific STAT3 deletion developed significantly less weight loss, albuminuria, and renal function impairment compared to Tg26 mice without STAT3 deletion. Tg26 mice with podocyte STAT3 deletion also had significantly less glomerular collapse, sclerosis, epithelial cell hyperplasia, podocyte dedifferentiation, and proinflammatory STAT3 target gene expression; and tubulointerstitial changes of HIVAN, including tubular atrophy, degeneration, apoptosis, and lymphocyte infiltration, were also significantly reduced compared to Tg26 mice without STAT3 deletion. CONCLUSION: Development of glomerular as well as tubulointerstitial injuries in the Tg26 HIVAN model is dependent on podocyte STAT3 expression. Inhibition of STAT3 could be a potential adjunctive therapy for the treatment of HIVAN.

Expression of HIV transgene aggravates kidney injury in diabetic mice.

With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wild-type mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease.

Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.

Despite intensive antihypertensive therapy there was a high incidence of renal end points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the nonmuscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers, were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dl during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.

Glomerular MYH9 expression is reduced by HIV-1.

BACKGROUND: The continuing disease burden of HIV-associated nephropathy (HIVAN) warrants better elucidation of its pathogenic mechanisms. Given that loss of MYH9 function causes a Mendelian renal disease, we hypothesized that renal expression of MYH9 is down-regulated by HIV-1 in HIVAN pathogenesis. METHOD AND RESULTS: Using immunofluorescence, we determined that glomerular expression of MYH9 was reduced in the kidneys of HIV-1 transgenic mice. We further determined that Myh9 expression was reduced in HIV-1 transgenic podocytes, statistically significantly at the protein level, and that MYH9 expression was significantly reduced at protein and message level in human podocytes transduced with HIV-1. In analyzing expression in human tissue, we confirmed that MYH9 is abundantly expressed in glomeruli, and podocytes specifically. Finally, we found that MYH9 expression was significantly reduced in human glomeruli in the setting of HIVAN. CONCLUSION: We conclude that the podocyte host response to HIV-1 includes down-regulation of MYH9 expression, and hypothesize that this down-regulation might play a role in the pathogenesis of HIVAN.

Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.

Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.

Recent progress in HIV-associated nephropathy.

The classic kidney disease of HIV infection, HIV-associated nephropathy (HIVAN), is an aggressive form of collapsing focal segmental glomerulosclerosis with accompanying tubular and interstitial lesions. HIVAN was first described among African-Americans and Haitian immigrants with advanced HIV disease, an early suggestion of a strong genetic association. This genetic susceptibility was recently linked to polymorphisms on chromosome 22 in individuals of African descent. The association with advanced HIV infection and evidence from HIV-transgenic mice suggested the possibility that HIV directly infects the kidney and that specific HIV gene expression induces host cellular pathways that are responsible for HIVAN pathogenesis. Although combination antiretroviral therapy has substantially reduced the impact of HIVAN in the United States, continued growth of the HIV epidemic in susceptible African populations may have important public health implications. This article reviews recent progress in the pathogenesis and treatment of HIVAN and describes the changing epidemiology of HIV-related kidney disease.