First case report of PLA2R-related monotypic (IgG-κ positive) membranous nephropathy concurrent with leukocyte chemotactic factor 2 amyloidosis.

BACKGROUND: Membranous nephropathy (MN) is a major pattern of nephrotic syndrome (NS) in adults. Some MN have secondary causes and some may be accompanied with other glomerular diseases. MN patients coexisting with amyloidosis are very rare, and mostly was polytypic MN. Herein, we describe the first report which identifying monotype PLA2R-MN (κ light chain) concurrent with leukocyte chemotactic factor 2 amyloidosis (ALECT2). This rare case highlights the importance of renal pathology for diagnosis. CASE PRESENTATION: We describe a case of a 60-year-old male patient with persistent proteinuria and low serum albumin for nine months. No monoclonal component was revealed by serum and urine immunofixation electrophoresis but serum PLA2R antibody was positive. The patient was empirically treated with Leflunomide and Losartan, but edema was not improved. The diagnosis of renal pathology is PLA2R-related monotypic (IgG-κ positive) MN concurrent with ALECT2. Methylprednisolone, cyclosporine A and anticoagulant (rivaroxaban) were prescribed resulting in a complete remission of NS. CONCLUSIONS: MN patients concurrent with ALECT2 presented massive proteinuria or NS. When nephrotic range proteinuria is present in ALECT2, it is important to consider that it may be due to a concomitant underlying nephropathy especially MN and treated according to MN will get good therapeutic effect.

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension.

BACKGROUND AND OBJECTIVES: Malignant hypertension (MHT) characterized by acute hypertension with retinopathy or multiorgan damage, is a severe form of hypertensive emergency and associated with target organ involvement and poor kidney outcome. However, the underlying mechanisms are unclear. METHODS: Eighty-four patients with acute severe hypertension from the Nephrology Department and Emergency Department in a single center during January 2016 and December 2017 were prospectively enrolled and divided into MHT ( n  = 48) and non-MHT ( n  = 36) subgroups according to target organ evaluation. Forty healthy controls were recruited. Serum soluble Fms-like tyrosine kinase-1 (sFlt-1) levels and plasma ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity were examined at baseline and 12-month follow-up. Renal endpoints were defined as a significant decrease in the estimated glomerular filtration rate (eGFR) of more than 40% or the occurrence of end-stage renal disease. RESULTS: Serum sFlt-1 levels were persistently elevated in MHT. Baseline serum sFLT-1 levels were correlated with plasma ADAMTS13 activity and markers of target organ damage. Plasma ADAMTS13 activity was reduced in both MHT and non-MHT patients and recovered to the normal range at 12-month follow-up. During an average follow-up time of 53 ±â€Š13 months, the restoration of reduced ADAMTS13 activity was correlated with the improvement of kidney function and independently reduced the risk of renal endpoints. CONCLUSIONS: Abnormal angiogenesis and endothelial damage are involved in the pathophysiology of hypertensive emergency. Evaluation of ADAMTS13 and sFlt-1 may help in the diagnosis and assessment of MHT. Recovery of ADAMTS13 predicts better renal outcome in patients with hypertensive emergencies.

Risk factors of temperature increase after cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy.

Background: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the standard treatment for patients with peritoneal cancer (PC). Following CRS-HIPEC, patients may also face risks caused by whole body hyperthermia. This study analyzed the incidence of temperature increases following CRS-HIPEC and identified the attendant risk factors. Methods: A retrospective analysis was carried out among 458 patients who received CRS-HIPEC at the Fourth Hospital of Hebei Medical University between August 2018 and January 2021. The patients were divided into two groups according to post-HIPEC axillary temperature (≥38°C), with the demographics and the laboratory test results subsequently analyzed and compared, and the risk factors pertaining to temperature increases analyzed using univariate and multivariate logistic regression. Results: During CRS-HIPEC, 32.5% (149/458) of the patients with a temperature increase had an axillary temperature of not lower than 38°C, and 8.5% (39/458) of the patients with hyperpyrexia had an axillary temperature of not lower than 39°C. Female gender, gynecological malignancies, type of chemotherapy drug, increased postoperative neutrophil percentage, and a sharp drop in postoperative prealbumin were associated with the incidence of a temperature increase and axillary temperatures of >38°C. Among these factors, the type of chemotherapy drug was identified as an independent risk factor for a temperature increase during CRS-HIPEC. Conclusion: By determining the risk factors pertaining to temperature increases during CRS-HIPEC, medical staff can identify the attendant risks among the patients and thus take preventive measures in a timely manner to maintain the patient's body temperature at a stable level. This suggests that further clinical research should be conducted to build a risk-prediction model for temperature increases following CRS-HIPEC.

C3aR Antagonist Alleviates C3a Induced Tubular Profibrotic Phenotype Transition via Restoring PPARα/CPT-1α Mediated Mitochondrial Fatty Acid Oxidation in Renin-Dependent Hypertension.

BACKGROUND: Renin-dependent hypertension with tubulointerstitial injury remains a problem with high prevalence in the clinic. However, whether and how renin participates in tubulointerstitial injury remains incompletely understood. New evidence suggests that renin cleaves C3 into C3a and C3b. In the present study, we aimed to explore the role of renin-mediated C3a/C3a receptor (C3aR) signaling in renin-dependent hypertension-induced kidney injury and illustrate the detailed mechanisms. METHODS: C3a concentration changes in serum from healthy volunteers incubated with recombinant renin were detected by ELISA. C3aR expression in human tubular epithelial cells was evaluated in renal biopsy sections from malignant arteriolonephrosclerosis and benign arteriolonephrosclerosis patients. C3aR changes in human kidney 2 (HK2) cells were detected after the cells were treated with human serum, renin and aliskiren. The C3a analogue and C3aR antagonist SB290157 were used to stimulate HK2 cells to explore the downstream signaling of C3a/C3aR activation. For in vivo studies, two-kidney, one-clipped (2K1C) hypertensive rat model was established to simulate renin-dependent hypertension conditions. C3a and C3aR expression was detected in the clipped kidneys. SB290157 was injected intraperitoneally to block C3a/C3aR signaling in 2K1C rats. RESULTS: The results showed that renin cleaved C3 into C3a and activated C3a/C3aR signaling in tubular epithelial cells (TECs) from both humans and rats. In vitro results demonstrated that C3a/C3aR activation impaired peroxisome proliferator-activated receptor alpha (PPARα)/carnitine palmitoyltransterase-1alpha (CPT-1α)-mediated mitochondrial fatty acid oxidation (Mito FAO) in HK2 cells and induced HK2 cell transition to a profibrotic phenotype, which was inhibited by treatment with the C3aR antagonist SB290157. In vivo results showed that renin mRNA levels, C3a concentrations, C3aR levels and tubulointerstitial fibrosis increased concurrently in the clipped kidney cortex of 2K1C rats. Treatment with the C3aR antagonist SB290157 significantly mitigated the effect of renin induction of C3aR expression and alleviated renin-dependent hypertension-induced tubulointerstitial fibrosis by improving PPARα/CPT-1α-mediated Mito FAO in TECs, as well as inhibiting tubular profibrotic phenotype transition. CONCLUSIONS: Our results prove that renin activates C3a/C3aR signaling to promote renal tubulointerstitial fibrosis by impairing PPARα/CPT-1α-mediated tubular Mito FAO. SB290157 confers a potential therapeutic approach for renin-dependent hypertension-induced kidney injury.

Role of the retinoic acid receptor-α in HIV-associated nephropathy.

All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-α (RARα). Here, we report that Am580, a water-soluble RARα-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RARα-/- Tg26 mice developed more severe kidney and podocyte injury than did RARα+/- Tg26 mice. Am580 failed to ameliorate kidney injury in RARα-/- Tg26 mice, confirming our hypothesis that Am580 acts through RARα. Although the expression of RARα-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RARα in the kidney was not different between patients with HIVAN and minimal change disease. However, the tissue levels of retinoic acid were reduced in the kidney cortex and isolated glomeruli of Tg26 mice. Consistent with this, the expression of two key enzymes in the retinoic acid synthetic pathway, retinol dehydrogenase type 1 and 9, and the overall enzymatic activity for retinoic acid synthesis were significantly reduced in the glomeruli of Tg26 mice. Thus, a defect in the endogenous synthesis of retinoic acid contributes to loss of the protection by retinoic acid in HIVAN. Hence, RARα agonists may be potential agents for the treatment of HIVAN.

Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport's syndrome confirmed by skin biopsy.

BACKGROUND: The clinical and pathological features of Alport syndrome are characterized by abnormalities in the basement membrane collagen network which are composed of the α3, α4 and α5 chains of type IV collagen and usually associated with hearing loss and ocular lesions. The predominant form (85% of AS) is inherited as X-linked mode (XLAS) caused by mutations encoding the α5 chain of type IV collagen gene, COL4A5. Different mutations in the COL4A5 gene have been reported widely, but only a few mutations were identified in Chinese patients. METHODS: We studied 71 Chinese patients from 35 unrelated families with XLAS confirmed by skin biopsy. Genomic DNA was extracted from peripheral blood of all patients. All 51 exons of the COL4A5 gene were screened by direct sequencing for the probands. RESULTS: A total of twenty-five identified gene mutations were considered to be pathogenic, including 1 nonsense, 1 splice-site, 1 complex rearrangement, 5 small deletions, 2 small insertions and 15 missense mutations. Twenty-one mutations have not been reported previously. CONCLUSIONS: We have identified 25 pathogenic mutations in 35 Chinese families with XLAS. Skin biopsy is effective for the diagnosis of XLAS.

Identification of a novel WNK4 mutation in Chinese patients with pseudohypoaldosteronism type II.

BACKGROUND: It has been reported that mutations in WNK1 and WNK4 cause pseudohypoaldosteronism type II (PHA2), an autosomal dominant renal disease. WNK kinase proteins are expressed in the kidney and regulate ion transport including the thiazide-sensitive sodium chloride cotransporter (NCC). In this report, we screened 4 Chinese PHA2 pedigrees for WNK4 mutations, identified a novel mutation, and studied its effects on NCC protein trafficking in vitro. METHODS: The patients' genomic DNA was extracted from peripheral leukocytes. Sequence analysis was performed by PCR amplification of the 19 exons of WNK4. The wild-type or mutant WNK4 was coexpressed with NCC in HEK293 cells. We measured the effect of wild-type WNK4 compared to the mutant WNK4 on NCC protein surface expression. RESULTS: A novel missense mutation in WNK4, K1169E, was identified in 1 of the 4 pedigrees. Analysis of confocal images showed that K1169E lost its inhibitory effect on NCC surface expression compared to wild-type WNK4 when expressed in HEK293 cells, while it did not change NCC total protein expression. CONCLUSIONS: We identified an unreported disease-causing WNK4 missense mutation, K1169E, in 1 Chinese PHA2 pedigree. This mutation appears to be a 'loss of function' of NCC inhibition and suggests that some important functional roles lie in the 2nd coiled-coil domain of WNK4.

ZLN005 protects against ischemia-reperfusion-induced kidney injury by mitigating oxidative stress through the restoration of mitochondrial fatty acid oxidation.

To date, the treatment of acute kidney injury (AKI) remains a difficult problem for clinicians. In the present study, we assessed whether ZLN005, a novel peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) agonist, can protect against ischemic AKI in vivo and in vitro. Notably, ZLN005 treatment significantly alleviated Ischemia-reperfusion (I/R)-induced tubular injury and reversed the decrease in hypoxia-reoxygenation-induced cell viability by restoring PGC-1α expression in a dose-dependent manner. This beneficial effect of ZLN005 was associated with the preservation of mitochondrial fatty acid oxidation (MitoFAO) and the alleviation of oxidative stress. Cotreatment with etomoxir, a specific inhibitor of carnitine palmitoyltransferase-1α (CPT-1α) activity, or CPT-1α siRNA abrogated ZLN005-induced antistress responses by mitigating reactive oxygen species production and decreasing apoptosis under ischemia-hypoxia conditions by suppressing MitoFAO. Further studies revealed that activation of endoplasmic reticulum (ER) stress may be involved in the effect of CPT-1α inhibition observed in vivo and in vitro. Collectively, our results suggest that ZLN005 confers a protective effect on I/R-induced kidney injury by mitigating ER stress through the restoration of MitoFAO by targeting PGC-1α.

Reduction of Stat3 activity attenuates HIV-induced kidney injury.

HIV-1 Nef induces podocyte proliferation and dedifferentiation by activating the Stat3 and MAPK1,2 pathways. Activation of Stat3 also occurs in human kidneys affected by HIV-associated nephropathy (HIVAN), but its contribution to the development of HIVAN is unknown. Here, we generated HIV-1 transgenic mice (Tg26) with either 75% Stat3 activity (Tg26-SA/+) or 25% Stat3 activity (Tg26-SA/-). The kidneys of Tg26-SA/+ mice, but not Tg26-SA/- mice, showed increased Stat3 phosphorylation. The Tg26-SA/+ phenotype was not different from Tg26 mice, but Tg26-SA/- mice developed significantly less proteinuria, glomerulosclerosis, and tubulointerstitial injury. Tg26-SA/+ mice exhibited reduced expression of podocyte differentiation markers and increased expression of VEGF and proliferation markers as compared to Tg26-SA/- mice. Primary podocytes isolated from Tg26-SA/+ mice showed increased Stat3 phosphorylation and reduced expression of podocyte differentiation markers. The tubulointerstitial compartment and isolated tubules of Tg26-SA/+ mice also had increased Stat3 phosphorylation and expression of Stat3 target genes. We confirmed that the expression of the HIV-1 transgene and reduction of Stat3 activity did not affect T and B cell development. In conclusion, Stat3 plays a critical role in the pathogenesis of HIVAN.

Clinical value of multiorgan damage in hypertensive crises: A prospective follow-up study.

Hypertensive crises are associated with high rates of target organ complications and poor outcomes. A recent shift from the definition of malignant hypertension to hypertension-multiorgan damage (MOD) contributes to the diagnosis and management of hypertensive crises. Here, we prospectively included 166 adult (≥18 years old) patients with hypertensive crises (blood pressure >180/120 mm Hg). Target organs and causes of hypertension were assessed. Patients who were diagnosed with malignant hypertensive retinopathy, the absence of malignant hypertensive retinopathy but the presence of damage to at least 3 organs, and the absence of both retinopathy and MOD were classified as the malignant hypertension (n = 48), hypertension-MOD (n = 42), and hypertension without MOD (n = 76) groups, respectively. Patients were followed to evaluate renal and cardiovascular prognoses. At baseline, patients with malignant hypertension had worse renal function, higher level of albuminuria, and more severe microvascular damage than those with hypertension-MOD. Both had similar proportions of malignant arteriolar nephrosclerosis (83% vs 64%), left ventricular hypertrophy (90% vs 88%), abnormal repolarization (71% vs 60%), and left ventricular dysfunction (12% vs 21%). At the twenty months of follow-up, both the malignant hypertension and hypertension-MOD groups had similar blood pressure control rates and proteinuria. Both groups had worse renal outcomes than the hypertension without MOD group (P = .002). Patients with hypertension-MOD (HR = 0.67, [95% CI: 0.30-1.46], P = .31) had similar renal event-free survival than patients with MHT after adjustments of age, sex, blood pressure, and proteinuria control. These results suggest that in hypertensive crises, both malignant hypertension and hypertension-MOD have impact on adverse renal outcomes.

Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy.

Recent studies suggest that Stat3, a transcription factor that mediates cytokine signaling, plays a critical role in the pathogenesis of diabetic nephropathy. Complete Stat3 gene knockout is embryonic lethal; therefore, we crossed Stat3+/- mice with Stat3 mutant mice (SA/SA) that lack full Stat3 activity. This strategy generated Stat3SA/- mice (25% activity) and Stat3SA/+ mice (75% activity), which were made diabetic using streptozotocin in order to define the role of Stat3 in diabetic kidney disease. While the glomerular number was not different between these two groups of mice, the diabetic SA/- mice had significantly less proteinuria, mesangial expansion, glomerular cell proliferation, and macrophage infiltration than the diabetic SA/+ mice. The reduction in Stat3 activity did not affect glomerular hyperfiltration seen after the induction of diabetes, as it was increased to the same degree in both groups of mice. Phosphorylation of Stat3 was markedly increased in the glomeruli of diabetic SA/+ mice compared to diabetic SA/- mice. The expression of inflammatory markers, IL-6, MCP-1, and activated NF-kappaB; type IV collagen, TGF-beta, and ICAM-1 mRNA; or type IV collagen and TGF-beta protein, were all found to be significantly less in glomeruli isolated from diabetic SA/- mice, as compared with diabetic SA/+ mice. Our study shows that Stat3 plays a critical role in the regulation of inflammation and abnormal matrix synthesis at an early stage of DN.

HIV-1 upregulates VEGF in podocytes.

HIV-associated nephropathy (HIVAN) is characterized by collapsing FSGS. Because transgenic mice with podocyte-specific overexpression of the vascular endothelial growth factor 164 (VEGF164) isoform also develop collapsing FSGS, we sought to determine whether VEGF plays a role in HIVAN. Compared with controls, immunohistochemistry revealed that kidneys from HIV-1-transgenic mice (Tg26) and from patients with HIVAN had greater expression of both VEGF and its transcriptional regulator, hypoxia-inducible factor 2alpha (HIF-2alpha). Similarly, mRNA and protein levels of VEGF and HIF-2alpha were increased in HIV-infected podocytes in vitro, and this transcriptional upregulation was found to be stimulated by the HIV viral protein Nef in a Src kinase-and Stat3-dependent manner. HIV-1 also upregulated VEGFR2 and its co-receptor neuropilin-1 and suppressed the expression of semaphorin 3a in the podocyte. Exogenous VEGF stimulated proliferation and de-differentiation of podocytes, which are features of collapsing FSGS, and VEGFR2 neutralizing antibodies reversed these features in podocytes infected with HIV-1 or isolated from Tg26 mice. In conclusion, HIV-1 induces VEGF and VEGFR2 expression in podocytes, and this may be a critical step in the pathogenesis of HIVAN.

Inhibition of neddylation plays protective role in lipopolysaccharide-induced kidney damage through CRL-mediated NF-κB pathways.

It has been shown that NF-κB signaling path is very effective pharmacological target for the treatment of various inflammatory diseases, including bacterial infection-associated acute kidney injury (AKI), which remains a main cause of disability and death in patients. Notably, IκB, the upstream molecular of NF-κB, plays an important role by inhibiting NF-κB activity, and IκB is regulated by cullin-RING E3 ligases (CRLs)-mediated proteasomal degradation. Therefore inhibition of CRLs-mediated neddylation and degradation of IκB would prevent NF-κB-mediated inflammation. MLN4924, a potent neddylation-inhibiting pharmacological agent, has been shown to have significant protective effects against lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production through restriction of the CRL-mediated NF-κB pathway. However, it is still unclear whether MLN4924 plays a protective role through its anti-inflammatory properties in sepsis-induced AKI. In the current research, we explored whether MLN4924 have anti-inflammatory action in LPS-induced AKI mice. Our results show that MLN4924 dramatically decreased the cytotoxicity of LPS and inhibited LPS-induced synthesis and release of pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1ß, in HK2 cells, a renal tubular cell line. In addition, MLN4924 inhibited Nedd8-activating enzymes, which broke the process of cullin proteins neddylation and subsequent CRL target proteins degradation. The MLN4924-induced degradation of CRL attenuated the phosphorylation modification of IκB and IKK-α/ß and blocked the nuclear translocation of P50-NF-κB and P65-NF-κB in HK2 cells under LPS stimulation. Finally, our in vivo results show that MLN4924 protected against LPS-induced AKI at relatively low doses. Collectively, these results suggest that pharmacologically blocking neddylation by MLN4924 results in the suppression of pro-inflammatory cytokines generation through the CRL/NF-κB pathway in LPS-stimulated HK2 cells, and attenuated renal inflammation in LPS-induced AKI.

Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α.

In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1α during hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1α can regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α.

Treatment and prognosis of primary focal segmental glomerulosclerosis.

This study aimed to analyze the treatment, clinical outcomes, and risk factors that affect the prognosis of patients with primary focal segmental glomerulosclerosis (FSGS) and to provide theoretical evidence for various treatment options in these patients. The study reviewed the clinical, laboratory, and pathological data of 168 patients with primary FSGS treated at Ruijin Hospital between January 2002 and October 2011. Of these patients, 108 were male (64.3%) and 60 were female (35.7%). The median age of disease onset was 38 years (range 12-78 years). The median case history was 10 months (range 4 days to 30 years). The mean proteinuria level was 2.3 ± 0.6 g/day. 75 (44.6%) patients had nephrotic syndrome. The mean serum creatinine was 108.1 ± 8.9 µmol/l. Over a follow-up period of 25.3 ± 11.4 months, end-stage renal failure occurred in 4 patients, and all 4 survived. In the group treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, the following factors were identified as risk factors for experiencing a 50% increase in serum creatinine over the baseline: a baseline eGFR <60 ml/min, proteinuria >1 g/day during the follow-up period, glomerular sclerosis >grade 1, and tubulointerstitial lesions >stage 1. In the group treated with steroids, patients who achieved a stable remission had better preserved renal function and milder glomerular sclerosis than steroid-dependent patients (p < 0.01). Steroid-resistant FSGS patients had a worse histological severity of glomerular sclerosis than steroid-dependent patients (p < 0.01). The prognosis of FSGS was correlated with the amount of proteinuria, the level of serum creatinine, and the severity of glomerular sclerosis and tubulointerstitial lesions. Steroids may be more effective in those who have better preserved renal function and milder glomerular sclerosis.

Changing spectrum of biopsy-proven primary glomerular diseases over the past 15 years: a single-center study in China.

The prevalence of chronic kidney disease (CKD) is reported to be 10.8-11.8% of the Chinese population. With economic development and longer life expectancy, the spectrum of CKD etiology has kept changing. Primary glomerular diseases (PGD) are still the most common renal diseases in China. To investigate the changing pattern of PGD in China, we retrospectively analyzed consecutive native renal biopsies performed in our hospital from 1997 to 2011. The patients were grouped according to a 3-year interval, 1997-1999 (period 1), 2000-2002 (period 2), 2003-2005 (period 3), 2006-2008 (period 4), 2009-2011 (period 5), and divided into three age groups (<20, 20-59, and ≥60 years old). 8,909 qualified cases were enrolled in this study. Among 8,909 specimens, 6,337 (71.13%) were diagnosed as PGD, while this prevalence decreased significantly from 77.61% in 1997-1999 to 66.73% in 2006-2008. IgA nephropathy (IgAN) was the most common PGD (36.66%), without any significant difference in the 5 periods (p = 0.185). IgAN was the most common PGD both in patients between the 20- to 59-year-old group (45.58%) and <20-year-old group (19.29%) as well. Membranous nephropathy (MN) was the most frequently found PGD in patients at age ≥60 years (39.64%). The frequency of MN was increased significantly from 6.48% in 1997-1999 to 22.79% in 2009-2011 (p < 0.001). The proportion of elderly patients increased significantly from 3.18% in 1997-1999 to 15.21% in 2009-2011 (p < 0.001). The prevalence of endocapillary proliferative glomerulonephritis (EnPGN) has decreased since 1997. PGD has remained the most common renal disease in China, although with a descending trend. The spectrum of PGD is different in different age groups. The frequency of EnPGN has decreased significantly, while that of MN has increased significantly.

HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein.

The ability of the human immunodeficiency virus, type 1 (HIV-1) protein Nef to induce cytoskeleton changes in infected host cells is a key event in viral replication. In renal podocytes, we found that Nef induced loss of stress fibers and increased lamellipodia, pathological changes leading to proteinuria in HIV-associated nephropathy. These morphological changes were mediated by Nef-induced Rac1 activation and RhoA inhibition. We identified a new interaction between Nef and diaphanous interacting protein (DIP), a recently described regulator of Rho and Rac signaling. We found that the Src homology 3 binding domain of DIP and the Nef PXXP motif were required for this interaction. Nef also interacts with Vav2 in podocytes. DIP and Vav2 both interact directly with Nef in a competitive manner. DIP interacts with p190RhoGAP, and intact DIP was required for Nef-induced phosphorylation of p190RhoGAP. DIP also interacts with Vav2, and although DIP enhanced baseline phosphorylation of Vav2, it was not required for Nef-induced Vav2 activation. In Nef-infected podocytes, Src kinase induces phosphorylation of DIP, p190RhoGAP, and Vav2, leading to RhoA inhibition and Rac1 activation. Inhibition of the Nef-induced signaling pathway by using a dominant negative of either Src or DIP or siRNA for DIP or p190RhoAGAP restored RhoA activity and stress fiber formation in Nef-infected podocytes, whereas siRNA for Vav2 reduced Rac1 activity and formation of lamellipodia. We conclude that in HIV-infected podocytes, Nef, through the recruitment of DIP and p190RhoAGAP to Nef-Src complex, activates p190RhoAGAP and down-regulates RhoA activity.

Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes.

Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. All-trans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/protein kinase A (PKA) and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1. atRA stimulated CREB and USF1 binding to the MKP1 gene promoter, as shown by gel shifting and chromatin immunoprecipitation assays. CREB directly mediated the early phase of atRA-induced MKP1 stimulation; whereas the later phase was mediated by CREB indirectly through induction of USF1. These findings were confirmed by a reporter gene assay using the MKP1 promoter with mutation of CRE or Ebox binding sites. Consistent with these findings, the biological effects of atRA on podocytes were inhibited by silencing either MKP1, CREB, or USF1 with small interfering RNA. atRA also induced CREB phosphorylation and MKP1 expression and reduced MAPK1,2 phosphorylation in kidneys of HIV type 1-infected transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of the Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1).