American journal of physiology. Renal physiology最新文献

Background: Approximately 30% of cancer patients experience kidney complications, which hinder optimal cancer management, imposing a burden on patients' quality of life and the healthcare system. The etiology of kidney complications in cancer patients is often attributed to oncological therapies. However, the direct impact of cancer on kidney health is underestimated. Our previous study demonstrated that metastatic lung cancer adversely alters the kidney, and exacerbates chemotherapy-induced nephrotoxicity, indicating lung cancer-kidney crosstalk. The current study examines whether this phenomenon is specific to the employed cancer model. Methods: Female and male mice of various strains were injected with different cell lines of remote organ cancer and their kidney tissues were analyzed for toxicity and fibrosis. Results: The impact of cancer on the kidney varied by cancer type. Breast cancer and specific subtypes of lung cancer, including KRAS- and EGFR-mutant cancer, pathologically altered kidney physiology and function in a manner dependent on the metastatic potential of the cell line. This was independent of mouse strain, sex, and cancer cell line origin. Moreover, tumor DNA was not detected in the renal tissue, excluding metastases to the kidney as a causative factor for the observed pathological alterations. Lewis lung carcinoma and B16 melanoma did not cause nephrotoxicity, regardless of the tumor size. Conclusion: Our results confirm cancer-kidney crosstalk in specific cancer types. In the era of precision medicine, further research is essential to identify at-risk oncology populations, enabling early detection and management of renal complications.

Macrophages are recognized as vital players in renal fibrosis, with a high degree of heterogeneity and plasticity, and the triggering receptor expressed on myeloid cell-2 (TREM-2) is highly expressed on macrophages and participates in the progression of tissue fibrosis. However, the mechanism by which TREM-2 mediates the progression of renal fibrosis is still unclear. Our study revealed that exosomes derived from TREM-2-deficient (TREM-2^-/-) macrophages suppressed the progression of fibrosis, as indicated by a greater matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) ratio at the protein level in secreted exosomes than in exosomes from wild-type (WT) macrophages in the fibrotic microenvironment. In addition, renal tubular epithelial cells (TECs) engulfed these nanoscale vesicles, and the expression of collagen I and α-smooth muscle actin (α-SMA) (a fibrosis-related marker) was obviously decreased. Through RNA-seq, we found that TREM-2^-/- macrophages increase the MMP-9/TIMP-1 ratio in their exosomes via the HSPa1b/AKT pathway. Notably, renal fibrosis was effectively alleviated in the obstructed kidneys of mice that received a renal pelvis injection of an adeno-associated virus (AAV-shTREM-2) containing the sequence used to silence TREM-2. However, VER-155008 (an inhibitor of HSPa1b) and Ly294002 (an inhibitor of AKT) reversed this effect. Moreover, polyclonal antibodies against TREM-2 also effectively relieved UUO-induced renal fibrosis. Overall, we validated that knocking down TREM-2 expression can inhibit the progression of renal fibrosis through a macrophage exosome-dependent pathway both in vitro and in vivo. Hence, our findings suggest that TREM-2 is a potential therapeutic target for CKD.

Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD), and there are currently no therapies for AKI. Proximal tubules (PT) are particularly susceptible to AKI, including due to nephrotoxins such as aristolochic acid I (AAI). Normal PT utilize fatty acid oxidation and branched chain amino acid (BCAA; valine, leucine, isoleucine) catabolism to generate ATP; however, in AKI, these pathways are downregulated. Our aim was to investigate the utility of a pharmacological activator of BCAA catabolism, BT2, in preventing nephrotoxic AKI. Mice were administered two injections of AAI 3 days apart to induce AKI, with or without daily BT2 treatment. Mice treated with BT2 had significantly protected kidney function (reduced serum creatinine and urea nitrogen), reduced histological injury, preservation of PT (Lotus lectin staining), and less PT injury (cytokeratin-20 staining) and inflammatory gene expression compared to mice with AAI alone. Mice with AKI had increased circulating BCAA and accumulation of BCAA in the kidney cortex. Leucine is a potent activator of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and mTORC1 signaling was activated in mice treated with AAI. However, BT2 reduced kidney cortical BCAA accumulation, and attenuated the mTORC1 signaling. In vitro, injured primary PT cells had compromised mitochondrial bioenergetics, but cells treated with AAI+BT2 had partially restored mitochondrial bioenergetics, and improved injury markers compared to cells treated with AAI alone. Thus, pharmacological activation of BCAA catabolism using BT2 attenuated nephrotoxic AKI in mice.

Acute kidney injury (AKI) is a common clinical syndrome with few effective treatments. Though the kidney can regenerate after injury, the molecular mechanisms regulating this process remain poorly understood. Pax2 and Pax8 are DNA-binding transcription factors that are upregulated after kidney injury. However, their function during the response to AKI remains incompletely defined. In this report, we develop a model of ischemic AKI in female mice with mosaic nephrons comprised of both Pax2 and Pax8 mutant and wildtype proximal tubule cells with fixed lineages. Each population therefore experiences identical physiological and injury conditions in the same animal. In these female mice, we show that before injury the S1 and S2 segments of the proximal tubule are depleted of Pax-mutant cells while mutant cells are preserved in the S3 segment. Retained S3 Pax-mutant cells develop a preconditioned phenotype that overlaps with gene expression signatures in AKI. In response to ischemic AKI, which most strongly damages the S3 proximal tubule, injury-resistant mutant S3 cells are more likely to proliferate. Pax-mutant cells then preferentially repopulate the S3 segment of the proximal tubule. Our results indicate that Pax2 and Pax8 are not required for regeneration of the S3 proximal tubule after ischemic AKI. Together, our findings indicate that Pax proteins play a critical role determining the segment-specific proximal tubule gene expression patterns that dictate vulnerability to ischemic injury.

HIV-associated nephropathy (HIVAN) is a kidney disease that affects mainly people of African ancestry with a high HIV-1 viral load. New antiretroviral therapies (ART) have been highly efficient in preventing and improving the outcome of HIVAN. However, providing chronic ART to children and adolescents living with HIV (CALWH) remains a significant challenge all over the world. More than 2.5 million CALWH, including those living in Sub-Saharan Africa, continue to be at high risk of developing HIVAN. Much of our understanding of the pathogenesis of HIVAN is based on studies conducted in transgenic mice and adults with HIVAN. However, CALWH may experience different health outcomes, risk factors, and susceptibilities to HIVAN in comparison to adults. This article reviews the progress made over the last 40 years in understanding the pathogenesis of HIVAN in CALWH, focusing on how the HIV virus, alongside genetic and environmental factors, contributes to the development of this disease. The landmark discovery that two risk alleles of the apolipoprotein-1 (APOL1) gene play a critical role in HIVAN has significantly advanced our understanding of the disease's pathogenesis. However, we still need to understand why renal inflammation persists despite ART and determine whether the kidney may harbor HIV reservoirs that need to be eliminated to cure HIV permanently. For these reasons, we emphasize reviewing how HIV-1 infects renal cells, affects their growth and regeneration, and discussing how inflammatory cytokines and APOL1 affect the outcome of childhood HIVAN.

In the kidney, the thick ascending limb (TAL) of the loop of Henle plays a vital role in NaCl homeostasis and blood pressure regulation. In human and animal models of salt-sensitive hypertension, NaCl reabsorption via the apical Na⁺/K⁺/2Cl^- cotransporter (NKCC2) is abnormally increased in the TAL. We showed that NaCl reabsorption is controlled by the presence of NKCC2 at the apical surface of TALs. However, the molecular mechanisms that maintain the steady-state levels of NKCC2 at the apical surface are not clearly understood. Here, we report that NKCC2 interacts with the F-actin cross-linking protein actinin-4 (ACTN4). We find that ACTN4 is expressed in TALs by Western blot and immunofluorescence microscopy. ACTN4 immunoprecipitated with NKCC2 and recombinant glutathione-S-transferase (GST)-ACTN4 pulled down NKCC2 from TAL lysates. ACTN4 is involved in endocytosis in other cells. Therefore, we hypothesized that ACTN4 binds apical NKCC2 and regulates its trafficking. To study the role of ACTN4 in NKCC2 surface expression, we silenced ACTN4 in vivo via shRNA or CRISPR/Cas9 system to decrease ACTN4 expression in TALs. We observed that silencing ACTN4 in vivo via shRNA or CRISPR/Cas9 system increased the amount of NKCC2 at the apical surface of TALs. Consistent with an increase in surface NKCC2, bumetanide-induced diuresis and natriuresis were enhanced by 35% after silencing of ACTN4 in vivo (AV-NKCC2-Cas9: 3,841 ± 709 vs. AAV-gRNA-ACTN4: 5,546 ± 622 µmol Na/8 h, n = 5, P < 0.05). We conclude that ACTN4 binds NKCC2 to regulate its surface expression. Selective depletion of ACTN4 in TALs using shRNA or CRISPR/Cas9 enhances surface NKCC2 and TAL-NaCl reabsorption, indicating that regulation of the ACTN4-NKCC2 interaction is important for renal NaCl reabsorption and could be related to hypertension.NEW & NOTEWORTHY ACTN4 function and dysfunction in glomerular podocytes have been extensively studied. However, the function of ACTN4 in the nephron has not been studied. Our paper shows for the first time that ACTN4, in the nephron, regulates NaCl reabsorption in part by affecting NKCC2 surface expression. Protein-protein interactions between ACTN4 and NKCC2 seem to mediate NKCC2 endocytosis in TALs. When ACTN4 was silenced in the TAL in vivo using CRISPR/Cas9 or shRNAs, surface NKCC2 and NaCl reabsorption increased.

In the present study, we examined whether chronic intracerebroventricular (ICV) leptin administration protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Twelve-week-old male rats were implanted with an ICV cannula into the right lateral ventricle, and 8-10 days after surgery, leptin (0.021 µg/h, n = 8) or saline vehicle (0.5 µL/h, n = 8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On day 8 of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle-treated group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (fourth day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. UIR-Leptin-treated rats showed reduced right and left kidney weights (right: 1,040 ± 24 vs. 1,281 ± 36 mg; left: 1,127 ± 71 vs. 1,707 ± 45 mg, for UIR-Leptin and UIR-PF, respectively). ICV leptin infusion improved GFR (0.50 ± 0.06 vs. 0.13 ± 0.03 mL/min/g kidney wt) and reduced kidney injury scores. ICV leptin treatment also attenuated the reduction in circulating adiponectin levels that was observed in UIR-PF rats and increased the circulating white blood cells count compared with UIR-PF rats (16.3 ± 1.3 vs. 9.8 ± 0.6 k/µL). Therefore, we show that leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and injury in a model of ischemia/reperfusion-induced AKI.NEW & NOTEWORTHY A major new finding of this study is that chronic activation of leptin receptors in the CNS markedly attenuates acute kidney injury and protects against severe renal dysfunction after ischemia/reperfusion, independently of leptin's anorexic effects.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease, and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.