Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Abstract

ŝĂbĞtic nephropathy is a leading cause of end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality worldwide in ƉĂtiĞnƚƐ with type 2 diabetes mellitus. The mechanisms behind the pathophysiology of DN are complex and cŽntinƵĞ to be not fully understood. Both metabolic (hyperglycaemia) and haemodynamic ĂůƚĞrĂtiŽnƐ interact ƐynĞrŐŝƐticĂůůy͕ and have been reported to ĂctivĂƚĞ local RAAS rĞƐƵůtinŐ in increased angiotensin-2. In spite the early and chronic treatment with cŽnvĞrtinŐ enzyme inhibitors and angiotensin receptor blocking drugs, the number of ƉĂtiĞnƚƐ reaching end stage renal disease and replacement therapy are increasing. Recently ĚŝīĞrĞnƚ pathways were proposed to be involved in the pathogenesis of ĚŝĂbĞtic nephropathy, including the autophagy process, Klotho and the ƐĞůĞctivĞ agonist vitamin D and his receptor. Under hyperglycemic stress especially in podocytes and proximal convolute tubule cells, there is decrease in the ƉrŽƚĞctivĞ autophagic process and increase in cellular damage. α-Klotho is a mƵůtiĨƵnctiŽnĂů protein highly expressed in the kidney. The klotho protein has endogenous Ănti ĮbrŽtic ĨƵnctiŽn via antagonism of Wnt/β-catenin signaling, which promotes ĮbrŽŐĞnĞƐŝƐ͕ ƐƵŐŐĞƐtinŐ that loss of Klotho in early stage of ĚŝĂbĞtic nephropathy may contribute to the progression of DN by accelerated ĮbrŽŐĞnĞƐŝƐ͘ The ƐĞůĞctivĞ vitamin D agonist and his receptor, play a ƉrŽƚĞctivĞ pathway in ĚŝĂbĞtic nephropathy. A key rĞnŽͲ ƉrŽƚĞctivĞ ĨƵnctiŽn of vitamin D is to reduce albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This ĂntiͲ ƉrŽƚĞŝnƵrŝc ĞīĞcƚ and the ĚĞcĞůĞrĂtiŽn of DN progression is mediated primarily via the blocking of the renin angiotensin aldosterone system. In this review we will discuss the ĚŝīĞrĞnƚ new mechanisms involved in ĚŝĂbĞtic nephropathy and future ƚŚĞrĂƉĞƵtic agents like the mTorc1 blocker, Rapamycin, that can upregulate the autophagy process, the new sodium-glucose transport inhibitors and Paricalcitol, the ƐĞůĞctivĞ ĂctivĞ vitamin D.