Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

Figures

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  Figure 1. The renin-angiotensin-aldosterone system (RAAS) is a key hormonal axis in the pathogenesis of arterial hypertension. The RAAS combines a regulatory network, including angiotensin II (Ang II) and aldosterone, which increase systemic blood pressure through a concerted mechanism. Angiotensinogen is enzymatically cleaved by renin and angiotensin-converting enzyme (ACE) to generate Angiotensin II, which, mainly via the Ang II receptor 1 (AT1R), stimulates the secretion of aldosterone, acts as a vasoconstrictor and leads to renal tubular retention of NaCl and water. For simplification, the negative feedback loop, which physiologically limits an excess activation of these pathways, is not included in this graph. Besides Ang II, endothelin 1 and increased sympathetic activity, which may be induced by RAAS activation or independent stimuli, also contribute to systemic vasoconstriction and increased peripheral resistance.

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  Figure 2. The immune system closely interacts with hormonal and environmental modifiers to control blood pressure. The immune system plays an important role in the pathogenesis of arterial hypertension and hypertensive end-organ damage. Lifestyle factors, such as the dietary nutrient composition and sodium intake directly, and via alterations in the gut microbiome, have influence on the cellular compositions of the immune system. Distinct immune cell subtypes, such as IL17 producing Th17 lymphocytes contribute to increased blood pressure. In parallel, existing arterial hypertension and Ang II favor Th17 polarization of T lymphocytes. Besides the effect of immune cells on blood pressure, the balance of various cells from the adaptive and innate immune system, including lymphocytes and macrophages is critical for end organ damage.

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  Figure 3. A complex network of various molecular pathways contributes to cellular adaptions, injury, and regenerative capacity in hypertensive kidney injury. In arterial hypertension, the cells in the kidney are exposed to various extracellular stimuli, including hormones, such as Ang II, altered hemodynamics with increased perfusion pressure, and potentially decreased oxygen supply and activated immune cells, which in turn secrete different cytokines. These stimuli affect all renal cell types: Nephron forming renal epithelial cells, endothelial cells, stroma, and immune cells. Although the net effect on injury and repair is highly cell type- and context-dependent, there are several parallels regarding the involved molecular signaling pathways. These pathways, or rather, signaling networks, are highly interrelated. For example, AT1R-mediated Ang II signaling, the Hippo pathway, pro- inflammatory signaling, including IL17 secretion and activation of TGFβ associated profibrotic signaling closely interact. Mechano-transduction and Hippo signaling, among others, influence the cytoskeletal integrity. Hypoxia-inducible factor (HIF) is stabilized by hypoxia, induces metabolic adaptions and may…