RESUMEN
Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world's population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.
Asunto(s)
COVID-19 , Enfermedades Cardiovasculares , Hipertensión , Enfermedades Renales , Enzima Convertidora de Angiotensina 2 , Apolipoproteína L1/metabolismo , Enfermedades Cardiovasculares/epidemiología , Femenino , Humanos , Hipertensión/epidemiología , Enfermedades Renales/epidemiología , Masculino , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina/fisiología , SARS-CoV-2RESUMEN
Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.
Asunto(s)
Apolipoproteína L1 , Enfermedades Renales , Compuestos Organotiofosforados , Ratones , Animales , Humanos , Apolipoproteína L1/genética , Células HEK293 , Variación Genética , Enfermedades Renales/genética , Ratones TransgénicosRESUMEN
COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Citocinas , Inhibidores de las Cinasas Janus , Enfermedades Renales , Apolipoproteína L1/genética , Azetidinas/farmacología , COVID-19/metabolismo , Citocinas/metabolismo , Células Endoteliales/metabolismo , Humanos , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/virología , Organoides/metabolismo , Purinas/farmacología , Pirazoles/farmacología , SARS-CoV-2/aislamiento & purificación , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacologíaRESUMEN
We postulated that kariomones and pheromones function to organize egg capsule deposition and breeding aggregations of mud snails (Ilyanassa obsoleta). Sexually active male and female mud snails were exposed to water-born odors from juvenile snails, nonaggregated female snails, oysters, egg capsule depositing snails, sexually active males, sexually active females, and copulating snails and tested for a follow response using a ring assay. Neither sex responded to juvenile odor or to odor of sexually inactive females. Snails turned and followed water born odors from oysters, when tested with the odors of sexually active males, sexually active females, and copulating pairs, we found sex-specific differences in responses. Sexually active females followed the odor of sexually active males and ignored sexually active female odor. Sexually active males followed the odor of sexually active females and ignored sexually active male odor. Both sexes followed the odor of copulating pairs and egg capsule depositing snails. Snail activities in breeding aggregations are organized by at least three pheromones and one kariomone, and reflect the multifunctionality of the aggregations.